Gel formulations for local drug release

ABSTRACT

The present invention relates to a composition comprising non-water soluble carbohydrates, wherein at least 50% of the non-water soluble carbohydrates are carbohydrates selected from derivatives of lactose, maltose, trehalose, raffinose, glucosamine, galactosamine, lactosamine, or derivatives of disaccharides with at least two pyranose saccharide units, trisaccharides, tetrasaccharides, or mixtures thereof, and wherein the composition is a liquid before administration into the human or animal body and increases in viscosity by more than 1,000 centipoise (cP) after administration, for use as a medicament.

FIELD OF THE INVENTION

The present invention provides controlled release of drugs from gelformulations for treatment of disease.

TECHNICAL BACKGROUND

Biomaterials for use as drug delivery systems have found wide interestfor treatment of multiple diseases and conditions in humans and animals,such as pain, inflammation, infection, allergy, and cancer. Advancedimaging techniques are furthermore important to diagnose patients andguide advanced treatments such as surgery and radiotherapy and newcontrast agents and biomaterials to guide such procedures are of greatimportance. The present invention provides injectable liquids that gelsor solidifies after administration to human or animal body after whichit provides a system for controlled drug release and/or acts as a tissuemarker for imaging by one or multiple imaging modalities.

Other patents and articles have described the use of biomaterials forcontrolled release of drugs for various applications. EP1212092 and U.S.Pat. No. 6,413,536 describe formulations for drug delivery based on ahydrophobic gel matrix consisting of organic solvent, a saccharide esterbased on sucrose derivatives such as SAIB or other poly-ols and one orseveral drugs. EP1173151B1 and U.S. Pat. No. 7,666,844 describesinjectable micro-implants for intramuscular or subcutaneous injection ofhormones, antidiabetic drugs, growth factors, and blood factors. Theinjectable formulations are based on derivatized carbohydrates. Theneedle formed solid micro-implants are thought to be so small, that theycan be injected by the patient him/herself by some manual device.EP1042339 and U.S. Pat. No. 6,352,722 describes isomers of derivativesof sucrose, lactose, cellobiose and trehalose for drug delivery. In thispatent, the medicinal molecules are incorporated in a solid carbohydratematrix by either mixing it with solvent following evaporation or bymelting the carbohydrates and then mixing them with the drug, whichresults in a solid matrix to be administered to the patient. Every yearmore than 12 million people are diagnosed with cancer worldwide and over7.5 million people die from cancer each year. These numbers are expectedto increase because of population growth and due to the lifestyle in theWestern world. There are four standard treatments of cancer; surgery,chemotherapy, radiotherapy and immunotherapy, which can be combined toprovide treatment benefit for patients. Radiotherapy is an importantpart of modern cancer treatment and more than 50% of cancer patientsreceive radiotherapy at least once. Modern radiotherapy relies onadvanced high precision planning, treatment equipment and imagingtechniques (such as, e.g., computed tomography (CT), positron-emissiontomography (PET) and magnetic imaging resonance (MRI)) in order todeliver high radiation doses to a precisely defined target in patients.Newer treatment regimes include photodynamic therapy, high intensityultrasound therapy, and methods for thermal ablation to create tissuedamage.

One of the main difficulties in external beam radiotherapy and othertherapies that rely on external energy delivery to tissues is that bothtumors and other tissue move significantly and unpredictably duringradiation; both within each single treatment, and during the wholecourse of treatment. These movements can be dramatic (e.g. several cmwithin seconds) and may be caused by various factors such asrespiration, bladder- and bowel filling, air passing colon, tumorshrinkage and set-up variation of the patient. One way of minimizingthis problem is the implantation of markers in or adjacent to the tumorallowing frequent imaging and treatment adaptation.

Ideally, a tissue marker should enable tracking of tissue movement; bevisible on several image modalities; be visible for an extended period(e.g., at least 4 weeks); be non-toxic; and be easy to insert.

Various attempts have been made for improvements within the field ofradiotherapy. EP1006935 describes a composition for controlled releaseof a substance WO9403155 describes a hydrogel composition prepared froma backbone bonded to a cross-linking agent. The hydrogels may be loadedwith therapeutic drugs and diagnostic labels, including X-ray contrastimaging agents for disease diagnostics and treatment. US20120065614discloses a hybrid system for bio imaging. Gold is bound into a matrixcomprising a hydrogel or polymer or similar. In US20100297007 asubstantially bi concave shaped nanoparticle is disclosed, thenanoparticle comprising an aqueous inner core and a hydrophilic outershell comprising an amphiphilic polymer.

Furthermore, US2009110644 discloses a nanoparticle consisting of apolymer which is a metal chelating agent coated with a magnetic metaloxide, wherein at least one active agent is covalently bound to thepolymer. In the documents US20100290995 and US2005036946, radio-opaquebiodegradable compositions are disclosed by modifying terminal groups ofsynthetic and natural biodegradable polymers such as polylactones withiodinated moieties and in SE403255 a contrast agent is disclosed thatcomprises a polymer comprising hydroxy- and/or carboxy- and/or aminogroups further comprising X-ray contrast giving iodo-substitutedaromatic groups. Further yet, the document WO 9519184 discloses airencapsulating micro particles formed by ionotropically gelling syntheticpolyelectrolytes such as poly(carboxylato-phenoxy)phosphazene,poly(acrylic acid), poly(methacrylic acid) and methacrylic acidcopolymers (Eudragit's) by contact with multivalent ions such as calciumions.

There are several drawbacks to the current clinical practice using solidmarkers and the methods described in the documents above. Installationof solid markers is invasive due to the large dimension of the solidimplant which may cause severe complications limiting is usefulness inradiotherapy. By combining gel-forming, low-viscosity solutions withsolid particles and/or organic X-ray contrast agents (or other imagingmodalities) injectable gels can be formulated with fine-tuned propertiesas these can be modified by multiply parameters with respect to the gelforming solution and the contrast agents used. The solid particles can,besides contributing to the overall contrast of the system, also carrypharmaceutical substances and control their release in a controlledmanner.

Unfortunately, radiotherapy is only able to provide local control of theprimary tumor and is not suitable for treating patients with metastaticdisease. However, by utilizing the weak immune stimulating effects thatradiotherapy provides, in combination with potent immune modulatingdrugs, it may be possible to cure patients with metastatic disease andobtain systemic tumor control. Cancer immunotherapy attempts tostimulate the immune system to reject and destroy tumors. Radiotherapy(RT) induces tumor cell death by several mechanisms, one represented byinduction of immunogenic cell death that leads to secretion ofimmunogenic proteins like Calreticulin and HMGB1, and small moleculeslike ATP. These factors activate antigen-presenting cells likemonocytes, dendritic cells (DC) and macrophages in the tumormicroenvironment. Furthermore, the cells phagocytose dead tumor cellsand cell components, and migrate to local lymph nodes to raise anantigen specific response against antigens from the resident dead tumorcells. Unfortunately, radiation alone does not induce a sufficientlyhigh immunogenic response to provide a specific immuno-dependenteradication of the cancer cells due to the immunosuppressiveenvironment, systemically as well as locally in the tumors. An effectcaused by M2 macrophages, Treg-cells, immature DCs and myeloid derivedsuppressor cells. However, a combination of radiotherapy withadministered Toll Like Receptor (TLR) agonists or other immunestimulating compounds can potentially provide a sufficiently high immunecell activation to induce a highly effective systemic response.

The combination of radiotherapy with chemotherapeutic drugs orradiosensitizers is also highly interesting for combination therapies ifefficient drug delivery systems were available.

One aim of the present invention is to provide new formulationscomprising gel-forming, low-viscosity systems that are easy toadminister parenterally, and wherein the present invention provides goodcontrol of drug release and potentially also visualization by one ormultiple imaging modalities.

SUMMARY OF THE INVENTION

The present invention relates to a composition comprising non-watersoluble carbohydrates, wherein at least 50% of the non-water solublecarbohydrates are carbohydrates selected from derivatives of lactose,maltose, trehalose, raffinose, glucosamine, galactosamine, lactosamine,or derivatives of disaccharides with at least two pyranose saccharideunits, trisaccharides, tetrasaccharides, or mixtures thereof, andwherein the composition is a liquid before administration into the humanor animal body and increases in viscosity by more than 1,000 centipoise(cP) after administration, for use as a medicament.

DESCRIPTION OF THE DRAWINGS

FIG. 1: In vitro studies of gel forming systems comprised of non-watersoluble carbohydrates

FIG. 2: In vitro release of isoniazide from 80% gel-compositions withdifferent hydrophobicities.

FIG. 3: In vitro release of fluorescein from 80% gel-compositions withdifferent hydrophobicities.

FIG. 4: In vitro release of Eosin Y from 80% gel-compositions withdifferent hydrophobicities.

FIG. 5: In vitro release of 5-fluorouracil (5-FU) from 80%gel-compositions with different hydrophobicity.

FIG. 6: In vitro release of 5-fluorouracil (5-FU) from 80%gel-compositions of lactose propionate formulations.

FIG. 7: In vitro release of 5-fluorouracil (5-FU) from 75% lactosepropionate+5% additive and 80% lactose propionate formulations.

FIG. 8: In vitro release of 5-fluorouracil (5-FU) from raffinose andtrehalose ester formulations consisting of 80% gel-forming carbohydratematerial and 20% solvent.

FIG. 9: In vitro release of 5-fluorouracil (5-FU) from glucosamine andmaltose ester formulations consisting of 80-65% gel-forming carbohydratematerial and 20-35% solvent.

FIG. 10: In vitro release of 5-fluorouracil (5-FU) from lactose estersformulations.

FIG. 11: In vitro release of 5-fluorouracil (5-FU) from lactoseisobutyrate formulations.

FIG. 12: In vitro release of gemcitabine HCl from 80% lactose esterformulations with different hydrophobicity.

FIG. 13: In vitro release of gemcitabine HCl from 80% maltose andglucosamine ester formulations.

FIG. 14: In vitro release of gemcitabine HCl from 80% maltose andglucosamine ester formulations.

FIG. 15. In vitro release of gemcitabine HCl from maltose propionateformulation.

FIG. 16: In vitro release of tirapazamine from 80% lactose esterformulations.

FIG. 17: In vitro release of resiquimod from 80% lactoseacetate:proprionate (1:1) formulations.

FIG. 18: In vivo gel stability evaluation of lactose isobutyrate gels byCT: CT-scans of mice injected with 25-30 uL of a lactoseisobutyrate:IodoSAIB:EtOH 80:5:15 (% w/w) or a lactoseisobutyrate:IodoSAIB:EtOH 75:5:20 (% w/w) gel formulation. The tumorstreated with radiotherapy were exposed to three radiations of 5 grayeach (day 2, day 3 and day 4 out of a period of 6 days). The whitearrows indicate the location of the radiopaque gel-depots.

FIG. 19: Histological cross section of the tumor area showing diffusionof Hoechst 33342 from the lactose isobutyrate gel depots. These imagesrepresent cryo-sections made from tumors taken out at 1 day and day 6post-injection. Intra-tumoral injection of the gel results in gaps intumor sections as can also be seen in the image. The white lineindicates the contour of the tumor section.

FIG. 20. In vitro release of gemcitabine HCl from lactoseacetate:propionate 1:1-triglyceride formulations.

FIG. 21. Release of lomeguatrib from lactose acetate:propionate 1:1 orlactose isobutyrate-triglyceride formulations.

FIG. 22 a): Release of Tirapazamine from lactose acetate:propionate 1:1and lactose isobutyrate-triglyceride formulations with and without 5-15%propylene carbonate or 1-0.25% cellulose acetate butyrate (Mn˜12.000).

FIG. 22 b): Release of Tirapazamine from lactose acetate:propionate 1:1and lactose isobutyrate-triglyceride formulations with and without 5-15%propylene carbonate or 1-0.25% cellulose acetate butyrate (Mn˜12.000).

FIG. 23: Release of temozolomide from lactose acetate:propionate 1:1 orlactose isobutyrate-triglyceride formulations with or without 5-10%organic solvent or 1-0.25% Cellulose acetate isobutyrate (CAB).

FIG. 24: Release of methotrexate from lactose acetate:propionate1:1-triglyceride formulations with 15-25% propylene carbonate.

FIG. 25 a): Release of 5-FU from lactose acetate:propionate 1:1 orlactose isobutyrate-triglyceride formulations.

FIG. 25 b): Release of 5-FU from lactose acetate:propionate 1:1 orlactose isobutyrate-triglyceride formulations.

FIG. 26 a): Release from high concentration 5-FU lactose isobutyrate gelformulations.

FIG. 26 b): Release from high concentration 5-FU lactose isobutyrate gelformulations.

FIG. 26 c): Release from high concentration 5-FU lactose isobutyrate gelformulations.

FIG. 26 d): Release from high concentration 5-FU lactose isobutyrate gelformulations.

FIG. 27 a): Figure b+zoom are named b 1) and b 2). Text for all 4figures: Release from high concentration 5-FU lactose acetate:propionate1:1 gel formulations.

FIG. 27 b 1): Release from high concentration 5-FU lactoseacetate:propionate 1:1 gel formulations.

FIG. 27 b 2): Release from high concentration 5-FU lactoseacetate:propionate 1:1 gel formulations.

FIG. 27 c): Release from high concentration 5-FU lactoseacetate:propionate 1:1 gel formulations.

FIG. 27 d): Release from high concentration 5-FU lactoseacetate:propionate 1:1 gel formulations.

FIG. 28 a): Release of 5-FU from lactose acetate:propionateregioisomer-triglyceride/EtOH formulations.

FIG. 28 b): Release of 5-FU from lactose acetate:propionateregioisomer-triglyceride/EtOH formulations.

FIG. 28 c): Release of 5-FU from lactose acetate:propionateregioisomer-triglyceride/EtOH formulations.

FIG. 29: Release of 5-FU from trehalose acetate:propionateregioisomer-triglyceride formulations.

FIG. 30a : Tumor growth curve and survival from a Fadu Xenograft mousemodel in vivo study with 5-FU release from Lactose isobutyrate:GTOformulations injected directly in tumor

FIG. 30b : Tumor growth curve and survival from a Fadu Xenograft mousemodel in vivo study with 5-FU release from Lactose isobutyrate:GTOformulations injected directly in tumor

FIG. 31a : Cumulative release, Resiquimod

FIG. 31b : Cumulative release, Resiquimod

FIG. 31c : Cumulative release, Imiquimod

FIG. 31d : Cumulative release, Imiquimod

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a composition comprising non-watersoluble carbohydrates, wherein at least 50% of the non-water solublecarbohydrates are carbohydrates selected from derivatives of lactose,maltose, trehalose, raffinose, glucosamine, galactosamine, lactosamine,or derivatives of disaccharides with at least two pyranose saccharideunits, trisaccharides, tetrasaccharides, or mixtures thereof, andwherein the composition is a liquid before administration into the humanor animal body and increases in viscosity by more than 1,000 centipoise(cP) after administration, for use as a medicament.

Definitions

“Non-water soluble carbohydrates” refers to carbohydrates that areinsoluble in water, which is defined as carbohydrates that precipitateswhen the concentration exceeds 0.1 M at 25 degrees Celsius.

In the context of the present invention, a “gel” is defined as a carriermatrix in which the detectable agent (contrast agent) or activepharmaceutical ingredient is dispersed and/or dissolved within. The term“gel” as used in the present invention includes systems such as gels oramorphous glass matrices, crystalline solids, amorphous solids, whichupon injection into a human or an animal increases viscosity where thecomposition changes from being liquid like to gel like in itsappearance.

In the context of the present invention, a “marker” or “tissue marker”is a detectable agent or composition which does not move, or stayssubstantially in the same position, for several days or weeks once ithas been administered or implanted into a specific site or tissue of amammalian body. A tissue marker can, for example, comprise one or moreX-ray contrast agents, radioactive compounds, paramagnetic compounds,fluorescent agents, ultrasound contrast agent, agents visible with PETimaging, or other detectable agents.

An “imageable tissue marker” or “imageable marker” comprises adetectable agent in a form and/or a sufficient amount to allow fordetection of the tissue marker by an external imaging modality ifadministered or implanted into a mammalian body. Exemplary externalimaging modalities include, but are not limited to, X-ray imaging, CTimaging, MRI, PET imaging, single photon emission computed tomography(SPECT) imaging, nuclear scintigraphy imaging, ultrasonography imaging,ultrasonic imaging, near-infrared imaging and/or fluorescence imaging.

With the term “carbohydrates”, as used herein, we refer tomonosaccharides, disaccharides and trisaccharides or oligosaccharides,including amino sugars.

With the term “hydrofobicity” we refer to the effect that molecule isseemingly repelled from water, which means that it has a very lowsolubility in water.

With the term “viscosity” we refer to that the viscosity of a fluid is ameasure of its resistance to gradual deformation by shear stress ortensile stress

With the term “gel-like” compound or material, as used herein, we referto any compound comprising some of the properties of a gel i.e. amaterial that exhibits limited flow when in the steady-state. By weight,gels are mostly liquid, yet they behave like solids due to athree-dimensional interactions within the liquid. It is the interactionswithin the fluid that gives a gel its structure (hardness) andcontributes to the adhesive stick. In this way gels are a dispersion ofmolecules of a liquid within a solid in which the solid is thecontinuous phase and the liquid is the discontinuous phase providing agel-like material with a higher viscosity than for that of a liquid.

The terms “drug”, “medicament”, “agent”, or “pharmaceutical agent” asused herein include, biologically, physiologically, or pharmacologicallyactive substances that act locally or systemically in the human oranimal body.

The terms “treating”, “treatment” and “therapy” as used herein referequally to curative therapy, prophylactic or preventative therapy andameliorating therapy. The term includes an approach for obtainingbeneficial or desired physiological results, which may be establishedclinically. For purposes of this invention, beneficial or desiredclinical results include, but are not limited to, alleviation ofsymptoms, diminishment of extent of disease, stabilized (i.e., notworsening) condition, delay or slowing of progression or worsening ofcondition/symptoms, amelioration or palliation of the condition orsymptoms, and remission (whether partial or total), whether detectableor undetectable. The term “palliation”, and variations thereof, as usedherein, means that the extent and/or undesirable manifestations of aphysiological condition or symptom are lessened and/or time course ofthe progression is slowed or lengthened, as compared to notadministering compositions of the present invention.

Detailed Description of the Invention

The formulation is preferably in the form adapted for parenteraladministration and/or for administration using topical route, and/or foradministration using intracavitary routes such as bladder, uterus, andvagina, and should preferably consist of pharmaceutically acceptableconstituents. The formulation that as such has a comparable lowviscosity is intended for injection in the body of a human or animal,where after the formulation becomes more viscous, i.e. it goes through asol-gel transition (liquid to gel) transition, due to the presence ofthe gel-forming system. It is preferred that the viscosity of theformulation after injection in the body of a human or animal increasesby at least 50%, such as at least 80%, such as at least 100% , or atleast 150%, or at least 200%, or at least 300%, or at least 500%, or atleast 750%, or at least 1000%, or at least 10,000%, or that theformulation becomes essentially solid (non-viscous).

The formulation is preferably adapted for injection via a thin needleused for injection into a body or surgical related procedures, such asbut not limited to biopsy. The viscosity of the gel-forming formulationbefore injection can be any suitable viscosity such that the formulationcan be parenterally administered to a patient.

Exemplary formulations include, but are not limited to, those having aviscosity (prior to administration/injection) lower than 10,000centipoise (cP), e.g. lower than 2,000 cP, such as 10 to 2,000 cP, suchas 20 to 1,000 cP, such as 150 to 350 cP, such as 400 to 600 cP, such as600 to 1,200 cP or such as 1,000 to 2,000 cP, or 10 to 600 cP, or 20 to350 cP, at 20° C. Alternative formulations include, but are not limitedto, those having a viscosity (prior to administration/injection) lowerthan 10,000 centipoise (cP), e.g. lower than 2,000 cP, such as 10 to2,000 cP, such as 20 to 1,000 cP, such as 150 to 350 cP, such as 400 to600 cP, such as 600 to 1,200 cP or such as 1,000 to 2,000 cP, or 10 to600 cP, or 20 to 350 cP, at 5° C. When referred to herein, the (dynamic)viscosity is measured at the specified temperature in accordance withthe method described in ASTM D7483. Gels in the present invention areformed by hydrophobic interactions and/or physical (non-covalent)cross-links by complexation, hydrogen bonding, desolvation, Van derWaals interactions, ionic bonding, combinations thereof, and the like,and may be initiated by mixing two precursors that are physicallyseparated until combined in situ, or as a consequence of a prevalentcondition in the physiological environment. Chemical (covalent) crosslinking may be accomplished by any of a number of mechanisms, includingfree radical polymerization, condensation polymerization, anionic orcationic polymerization, step growth polymerization,electrophile-nucleophile reactions, combinations thereof, and the like.

The gel forming compositions may be loaded with organic x-ray agentssuch as iodinated polymers or sugars and nanoparticles or submicronparticles either prior to or during gel formation, such as when the gelis in a liquid state or in transition to the gel-state, e.g., bydiffusion into the gel composition. These x-ray agents or particles mayeither be entrapped in the hydrogel matrix without any chemical bond, orthey may be bonded, non-covalently or covalently, to the gelcomposition. The organic x-ray agents may be one component in the geland the particles another component, where the particles are either acontrast agent for imaging by x-ray, MRI, PET, SPECT, fluorescence,proton radiation or ultrasound including HIFU, and/or containpharmaceutical agents. Pharmaceutical agents may be, but not limited to,radiosensitzers, chemotherapeutics, immunomodulators, anesthetics orhormones. MRI agents such as gadolinium may be a component in the gelforming systems. Pharmaceutical agents can furthermore be covalent ornon-covalently embedded in the gel. After injection, the gelled orsolidified formulation typically provides a well defined gel thatremains at the injection site for several days, weeks or months and maycontain an assembly of imaging contrast agents which provides contrastin e.g. X-ray imaging, and which may serve as a tissue marker, thus,enabling tracking of tissue or tumor movement during e.g. radiotherapyor surgical procedures.

The gel forming system may be used for aid or guidance of one or moreexternal or internal stimuli (or a combination of both). It may also beused in combination with external or internal stimuli to enhance thetherapeutic effect of the stimuli. In one interesting embodiment, thegel forming system may be used in combination with photodynamic therapy(PDT) in combination with a drug (photosensitizer or photosensitizingagent) with a specific type of light to kill cancer cells. In anotherembodiment, the gel forming system may be used in combination withhyperthermia based treatments such as high-intensity focused ultrasound(HIFU), radiofrequency thermal ablation (RFA) and laser-inducedinterstitial thermotherapy (LITT), but not limited to those. Inhigh-intensity focused ultrasound (HIFU) the gel forming system may beused to direct or aid in delivery of acoustic energy into the desiredtissue thereby destroying the diseased tissue by e.g. thermal ablation(coagulation necrosis). In another embodiment, the gel forming systemmay be used to direct or aid in insertion of the needle electrode intothe target site for use in radiofrequency thermal ablation (RFA). In yetanother embodiment, the gel forming system may be used to direct or aidin Laser-induced interstitial thermotherapy (LITT) to ensure correctlaser irradiation of the target tissue.

Gel Forming Component

Suitable gel-forming components include those composed of organicconstituents such as derivatized saccharides such as esterifiedsaccharides, derivatized polyols such as esterified polyols, polymers,lipids, peptides, proteins, low molecular weight gelators and non-watersoluble high-viscosity liquid carrier materials as well as combinationshereof.

In one specific embodiment of the invention the hydration sensitive gelforming component is hydrophobic saccharides. Preferred scaffolds aremonosaccharides, disaccharides, trisaccharides, or oligosaccharides.Other suitable alcohol moieties include those derived by removing one ormore hydrogen atoms from: monofunctional C1-020 alcohols, difunctionalC1-020 alcohols, trifunctional alcohols, hydroxy-containing carboxylicacids, hydroxy-containing amino acids, phosphate-containing alcohols,tetrafunctional alcohols, sugar alcohols, monosaccharides, anddisaccharides, sugar acids, and polyether polyols. More specifically,alcohol moieties may include one or more of: dodecanol, hexanediol, moreparticularly, 1,6-hexanediol, glycerol, glycolic acid, lactic acid,hydroxybutyric acid, hydroxyvaleric acid, hydroxycaproic acid, serine,ATP, pentaerythritol, mannitol, sorbitol, glucose, galactose, fructose,maltose, lactose, glucuronic acid, polyglycerol ethers containing from 1to about 10 glycerol units, polyethylene glycols containing 1 to about20 ethylene glycol units. Additionally, any oligosaccharide containingfrom 3 to about 6 monosaccharides may be used as the scaffold in thepresent invention. In general, the scaffold esters of the invention canbe made by reacting one or more alcohols, in particular one or morepolyols, which will form the alcohol moiety of the resulting esters withone or more carboxylic acids, lactones, lactams, carbonates, oranhydrides of the carboxylic acids which will form the acid moieties ofthe resulting esters. The esterification reaction can be conductedsimply by heating, although in some instances addition of a strong acidor strong base esterification catalyst may be used. Alternatively, anesterification catalyst such as stannous 2-ethylhexanoate or activationreagents such as N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC),N,N′-Dicyclohexylcarbodiimide (DCC),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and the like can be used.

The acyl groups forming the acyloxy substituents of the invention may beany moiety derived from a carboxylic acid. More particularly, the acylgroups of the compositions of the invention may be of the RCO—, where Ris optionally oxy-substituted alkyl of 2-10 carbon atoms which may belinear or branched hydrocarbons with one or more functional groupspresent in the chain. Using carboxylic acids and/or polyols of differentchain length and using carboxylic acids having oxy-substitution allowscontrol of the degree of hydrophilicity and of the solubility of theresulting ester. Such materials are sufficiently resistant todissolution in vivo that they are able to form stabile hydrophobic gels,which may encapsulate the acitive pharmaceutical ingredients and/or thecontrast agents of the present invention.

Suitable monosaccharides in either D or L-form include but are notlimited to the following structures, in which α,β anomeric mixtures atany ratio may exist: Glucosamine, Galactosamine, Mannosamine, Mannose,Rhamnose, Rhamnosamine, Galactose, Allose, Allosamine, Altrose,Altrosamine, Gulose, Gulosamine, Idose, Idosamine, Talose andTalosamine.

Suitable disaccharides, include but are not limited to the followingstructures in which α,β anomeric mixtures at any ratio may exist, andwhere the individual sugars may be linked by either α or β glycosidicbonds and the individual sugars can D or L: Galp-(1→2)-Glc,Galp-(1→3)-GlcN, Galp-(1→4)-Glc, Glcp-(1→4)-Glc, Glcp-(1→6)-Glc,Glcp-(1→2)-GlcN, Galp-(1→4)-ManN, Glcp-(1→4)-GalN, Manp-(1→3)-Glc,ManNp-(1→4)-Gal, GalNp-(1→3)-ManN, GlcNp-(1→6)-GalN, Rhamnp-(1→6)-Glc,Glcp-(1↔1)-Glcp, Talp-(1→4)-Glu, Glup (1→3)-Ido, GlcAlp-(1→4)-GlcN,GlcAlp-(1→6)-GlcN.

Suitable trisaccharides include but are not limited to the followingstructures in which α,β anomeric mixtures at any ratio may exist, andwhere the individual sugars can be linked by either α or β glycosidicbonds and the individual sugars can be D or L:Galp-(1→2)-Glcp-(1→3)-Galp, Galp-(1→4)-Glcp-(1→6)-GlcN,Galp-(1→4)-Glcp-(1→6)-Gal, Glcp-(1→4)-Glcp-(1→4)-Glcp,Glcp-(1→6)-Glcp-(1→6)-Glc, Galp-(1→6)-Glcp (1↔2)-Fruf,Glcp-(1→3)-Fruf-(2↔1)-Glcp, Galp-(1→4)-ManNp-(1→3)-Glu,Glcp-(1→4)-GalN-(1→2)-Man, Manp-(1→3)-Glcp-(1→4)-GlcN,ManNp-(1→4)-Galp-(1→3)-Glc, GalNp-(1→3)-ManNp-(1→6)-GlcN.Rhamnp-(1→6)-Glcp-(1→4)-GlcN, Galp-(1→6)-Glcp-(1↔1)-Glcp,Talp-(1→4)-Glup-(1→2)-Man, Glup (1→3)-Idop-(1→6)-Glu, GlcNp-(1→6)-GlcNp(1→4)-GlcN.

Suitable tetrasaccharides include but are not limited to the followingstructures in which α,β anomeric mixtures at any ratio may exist, andwhere the individual sugars can be linked by either α or β glycosidicbonds and the individual sugars can be D or L:Galp-(1→4)-Glcp-(1→6)-glcp-(1→4)-Glc,Galp-(1→4)-Glcp-(1→4)-Glcp-(1→4)-Glcp-(1→4)-Glc,Galp-(1→4)-Glcp-(1→4)-Galp-(1→4)-Glc,Glcp-(1→4)-Glcp-(1→4)-Glcp-(1→4)-Glc,Galp-(1→6)-Glcp-(1→6)-Galp-(1→6)-Glc,Galp-(1→6)-Glcp-(1→6)-Galp-(1→4)-Glc,Galp-(1→6)-Glcp-(1→6)-Glcp-(1→4)-Glc,GlcNp-(1→4)-GlcNp-(1→6)-GlcNp-(1→4)-GlcN,GlcNp-(1→6)-Galp-(1→6)-Glcp-(1↔2)-Fruf,Galp-(1→4)-Glcp-(1→3)-Fruf-(2↔1)-Glcp,Talp-(1→4)-Glup-(1→2)-Man-(1-3)-Glu, Glup(1→3)-Idop-(1→6)-Glup-(1→2)-Gal.

Solvent

The composition of the solvent (dispersion medium) should not beparticularly limited, and examples include biocompatible organicsolvents such as ethanol, ethyl lactate, propylene carbonate,glycofurol, N-methylpyrrolidone, 2-pyrrolidone, propylene glycol,acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, benzylalcohol, triacetin, dimethylformamide, dimethylsulfoxide,tetrahydrofuran, caprolactam, decylmethylsulfoxide, such as but notlimited to N-methyl-2-pyrrolidone, glycofurol, polyethylene glycol(PEG), benzyl benzoate, triglycerides, acetone, benzyl alcohol,N-(betahydromethyl) lactamide, butylene glycol, caprolactam,caprolactone, corn oil, decylmethylsulfoxide, dimethyl ether, dimethylsulfoxide, 1-dodecylazacycloheptan-2-one, ethanol, ethyl acetate, ethyllactate, ethyl oleate, glycerol, glycofurol (tetraglycol), isopropylmyristate, methyl acetate, methyl ethyl ketone, esters of caprylicand/or capric acids with glycerol or alkylene glycols, oleic acid,peanut oil, polyethylene glycol, propylene carbonate, 2-pyrrolidone,sesame oil, [±]-2,2-dimethyl-1,3-dioxolane-4-methanol, tetrahydrofuran,diethylene glycol monoethyl ether, carbitol, triacetin, triethylcitrate, and combinations thereof; or desirably fromtrichlorofluoromethane, dichlorofluoromethane, tetrafluoroethane(R-134a), dimethyl ether, propane, butane, and combinations thereof; orspecifically from caprylic/capric triglyceride, oleic acid,1-dodecylazacycloheptan-2-one and the like. Although the formulation canbe stably dispersed in these solvents (dispersion media), the solventsmay be further added with a saccharide derivatives of for example,triglycerides such as tri-pentanoyl glycerol, tri-octanoyl glycerol,tri-dodecanoyl glycerol, a monosaccharide such as glucose, galactose,mannose, fructose, inositol, ribose and xylose, disaccharide such aslactose, sucrose, cellobiose, trehalose and maltose, trisaccharide suchas raffinose and melezitose, and polysaccharide such as α-, β-, orγ-cyclodextrin, sugar alcohol such as erythritol, xylitol, sorbitol,mannitol, and maltitol, or a polyhydric alcohol such as glycerin,diglycerin, polyglycerin, propylene glycol, polypropylene glycol,ethylene glycol, diethylene glycol, triethylene glycol, polyethyleneglycol, ethylene glycol mono-alkyl ether, diethylene glycol mono-alkylether and 1,3-butylene glycol. Additives may furthermore be selectedfrom the group consisting of bioavailable materials such as amiloride,procainamide, acetyl-beta-methylcholine, spermine, spermidine, lysozyme,fibroin, albumin, collagen, transforming growth factor-beta (TGF-beta),bone morphogenetic proteins (BMPs), fibroblast growth factor (bFGF),dexamethason, vascular endothelial growth factor (VEGF), fibronectin,fibrinogen, thrombin, proteins, dexrazoxane, leucovorin, ricinoleicacid, phospholipid, small intestinal submucosa, vitamin E, polyglycerolester of fatty acid, Labrafil, Labrafil M1944CS, citric acid, glutamicacid, hydroxypropyl, isopropyl myristate, Eudragit, tego betain,dimyristoylphosphatidyl-choline, scleroglucan, and the like; organicsolvents such as cremophor EL, ethanol, dimethyl sulfoxide, and thelike; preservatives such as methylparaben and the like; sugars such asstarch and derivatives thereof, sugar-containing polyols such assucrose-mannitol, glucose-mannitol, and the like; amino acids such asalanine, arginine, glycine, and the like; polymer-containing polyolssuch as trehalose-PEG; sucrose-PEG, sucrose-dextran, and the like;sugar-containing amino acid such as sorbitol-glycine, sucrose-glycine,and the like; surfactants such as poloxamer of various molecularweights, Tween 20 Tween 80, Triton X-100, sodium dodecyl sulfate(SDS),Brij, and the like; sugar-containing ions such as trehalose-ZnSO₄,maltose-ZnSO₄, and the like; and bio-acceptable salts such as silicate,NaCl, KCl, NaBr, NaI, LiCl, n-Bu₄NBr, n-Pr₄NBr, Et₄NBr, Mg(OH)₂,Ca(OH)₂, ZnCO₃, Ca₃(PO₄)₂, ZnCl₂, (C₂H₃O₂)₂Zn, ZnCO₃, CdCl₂, HgCl₂,CaCl₂, (CaNO₃)₂, BaCl₂, MgCl₂, PbCl₂, AlCl₂, FeCl₂, FeCl₃, NiCl₂, AgCl,AuCl, CuCl₂, sodium tetradecyl sulfate, dodecyltrimethyl-ammoniumbromide, dodecyltrimethylammonium chloride, tetradecyltrimethyl-ammoniumbromide, and the like, but not limited to those.

In one embodiment of the present invention, the content of the additiveis from 1×10⁻⁶ -50 wt %, preferably 1×10⁻³ to 30 wt %, based on thetotal weight of the gel forming component(s).

Contrast Agents

Contrast may be achieved using organic x-ray contrast agents, such asradiopague agents such as iodinated compounds, which may be combinedwith chelators of MRI agents such as gadolinium, and/or combined withchelators of PET imaging agents such as copper-64, which may further becombined with solid inorganic particles. Chelators may be DOTA, EDTA, orDTPA and chelators will be non-covalently embedded or covalentlyconjugated to the gel-forming components. The combined contrast agentsshould preferably be visible by at least CT imaging. Preferred contrastagents are iodinated compounds such as polymers or sugar molecules suchas derivatives of glucose or sucrose or other oligosaccharides. Solidparticles may comprise, or consist of, one or more X-ray contrastagents, i.e., compounds that are able to block or attenuate X-rayradiation. Such compounds include transition metals, rare earth metals,alkali metals, alkali earth metals, other metals, as defined by theperiodic table. A metal or alkali metal may appear in non-oxidized orany of the existing oxidation states for the metal. These oxidationstates include monovalent cations, divalent cations, trivalent cations,tetravalent cations, pentavalent cations, hexavalent cations andheptavalent cations.

In one embodiment, the one or more X-ray contrast agents are selectedfrom Iodine (I), gold (Au), bismuth (Bi), gadolinium (Gd), iron (Fe),barium (Ba), calcium (Ca) and magnesium (Mg). In a particularembodiment, the detectable compound comprises one or more compoundsselected from the group of gold (Au) and bismuth (Bi). The one or moreX-ray contrast agents are typically present in metal form, in alloyform, in oxide form or in salt form.

It should be understood that besides iodinated compounds which providesa useful contrast for X-ray imaging, the formulation may also includesolid particles that are visible by X-ray imaging or other imagingmodalities than X-ray imaging. In one embodiment, the solid-particlesare furthermore visible by MR and/or PET imaging, or by other imagingmodalities.

In a particular embodiment, the gel-forming composition may furthercomprise a radioactive or paramagnetic compound for one or more imagingmodalities such as MRI, PET imaging, SPECT imaging, nuclear scintigraphyimaging, ultrasonography imaging, ultrasonic imaging, near-infraredimaging and/or fluorescence imaging.

In some interesting embodiments, the formulation according to any one ofthe preceding claims, contain solid particles that comprise one or moreradioactive, paramagnetic or ferromagnetic particles.

Moreover, individual particles may comprise two or more types ofcompounds which are visible in different imaging modalities.

Said radioactive compounds may comprise isotopes of Copper (⁶¹Cu, ⁶⁴Cu,and ⁶⁷Cu), Iodide (¹²³I, ¹²⁴I, ¹²⁵I, ³¹¹I), Indium (¹¹¹In), Technetium(^(99m)Tc), Rhenium (¹⁸⁶Re, ¹⁸⁸Re), Gallium (⁶⁷Ga, ⁶⁸Ga), Strontium(⁸⁹Sr), Samarium (¹⁵³Sm), Ytterbium (¹⁶⁹Yb), Thallium (²⁰¹Tl), Astatine(²¹¹At), Lutetium (¹⁷⁷Lu), Actinium (²²⁵Ac), Yttrium (⁹⁰Y), Antimony(¹¹⁹Sb), Tin (¹¹⁷Sn, ¹¹³Sn), Dysprosium (¹⁵⁹Dy), Cobalt (⁵⁶Co), Iron(⁵⁹Fe), Ruthenium (⁹⁷Ru, ¹⁰³Ru), Palladium (¹⁰³Pd), Cadmium (¹¹⁵Cd),Tellurium (¹¹⁸Te, ¹²³Te), Barium (¹³¹Ba, ¹⁴⁰Ba), Gadolinium (¹⁴⁹Gd,¹⁵¹Gd), Terbium (¹⁶⁹Tb), Gold (¹⁹⁸Au, ¹⁹⁹Au), Lanthanum (¹⁴⁰ La),Zirconium (⁸⁹Zr), Titanium (⁴⁵Ti) and Radium (²²³Ra, ²²⁴Ra), whereinsaid isotope of a metal radionuclide may appear in any of the existingoxidation states for the metal. These oxidation states includemonovalent cations, divalent cations, trivalent cations, tetravalentcations, pentavalent cations, hexavalent cations and heptavalentcations.

Said paramagnetic or ferromagnetic compounds may also be selected fromthe group of Scandium (Sc), Yttrium (Y), Lanthanum (La), Titanium (Ti),Zirconium (Zr), Hafnium (Hf), Vandium (V), Niobium (Nb), Tantalum (Ta);Chromium (Cr), Molybdenium (Mo), Tungsten (W), Manganese (Mn),Technetium (Tc), Rhenium (Re), Iron (Fe), Ruthenium (Ru), Osmium (Os),Cobalt (Co), Rhodium (Rh), Iridium (Ir), Nickel (Ni), Palladium (Pd),Platinum (Pt), Copper (Cu), Silver (Ag), Gold (Au), Zinc (Zn), Cadmium(Cd), Mercury (Hg), the lanthanides such as Lathanum (La), Cerium (Ce),Praseodymium (Pr), Neodymium (Nd), Promethium (Pm), Samarium (Sm),Europium (Eu), Gadolinium (Gd), Terbium (Tb), Dysprosium (Dy), Holmium(Ho), Erbium (Er), Thulium (Tm), Ytterbium (Yb), Lutetium (Lu)) and theactinides such as Actinium (Ac), Thorium (Th), Protactinium (Pa),Uranium (U), Neptunium (Np), Plutonium (Pu), Americium (Am), Curium(Cm), Berkelium (Bk), Californium (Cf), Einsteinium (Es), Fermium (Fm),Mendelevium (Md), Nobelium (No) and Lawrencium (Lr), wherein saidparamagnetic or ferromagnetic compounds may appear in any of theexisting oxidation states for the metal. These oxidation states includemonovalent cations, divalent cations, trivalent cations, tetravalentcations, pentavalent cations, hexavalent cations and heptavalentcations.

Said one or more radioactive, paramagnetic or ferromagnetic compoundsmay be covalently linked to gel-forming components or the nano-sizedparticles or non-covalently associated with the gel-forming componentsor nano-sized particles.

In one embodiment, the gel-forming components or nano-sized particlesfurther comprise one or more fluorophore compounds for near infraredfluorescence imaging. Said compounds may comprise a fluorescentproteins, peptides, or fluorescent dye molecules. Common classes offluorescent dyes include xanthenes such as rhodamines, rhodols andfluoresceins, and their derivatives; bimanes; coumarins and theirderivatives such as umbelliferone and aminomethyl coumarins; aromaticamines such as dansyl; squarate dyes; benzofurans; fluorescent cyanines;carbazoles; dicyanomethylene pyranes, polymethine, oxabenzanthrane,xanthene, pyrylium, carbostyl, perylene, acridone, quinacridone,rubrene, anthracene, coronene, phenanthrecene, pyrene, butadiene,stilbene, lanthanide metal chelate complexes, rare-earth metal chelatecomplexes, and derivatives of such dyes. Typical fluorescein dyesinclude 5-carboxyfluorescein, fluorescein-5-isothiocyanate and6-carboxyfluorescein; examples of other fluorescein dyes can be found,for example, in U.S. Pat. No. 6,008,379, U.S. Pat. No. 5,750,409, U.S.Pat. No. 5,066,580, and U.S. Pat. No. 4,439,356. The species may alsoinclude a rhodamine dye, such as, for example,tetramethylrhodamine-6-isothiocyanate, 5-carboxytetramethylrhodamine,5-carboxy rhodol derivatives, tetramethyl and tetraethyl rhodamine,diphenyldimethyl and diphenyldiethyl rhodamine, dinaphthyl rhodamine,rhodamine 101 sulfonyl chloride (sold under the tradename of TEXAS RED),and other rhodamine dyes. The species may alternatively include acyanine dye, such as, for example, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy. OrIRDye 800CW, IRDye 680LT, Qdot 800 nanocrystal, Qdot 705 nanocrystal orporphyrazine compounds

In another embodiment, the nano-sized particles further comprise orconsist of one or more gasses encapsulated in lipid, polymer orinorganic based particles for ultrasonography imaging. Said gasses maycomprise air, sulphur halides such as sulphur hexafluoride or disulphurdecafluoride; fluorocarbons such as perfluorocarbons; fluorinated (e.g.perfluorinated) ketones such as perfluoroacetone; and fluorinated (e.g.perfluorinated) ethers such as perfluorodiethyl ether. Representativeperfluorocarbons, which may for example contain up to 7 carbon atoms,include perfluoroalkanes such as perfluoromethane, perfluoroethane,perfluoropropanes, perfluorobutanes (e.g. perfluoro-n-butane, optionallyin a mixture with other isomers such as perfluoro-iso-butane),perfluoropentanes, perfluorohexanes and perfluoroheptanes;perfluoroalkenes such as perfluoropropene, perfluorobutenes (e.g.perfluorobut-2-ene) and perfluorobutadiene; perfluoroalkynes such asperfluorobut-2-yne; perfluorocycloalkanes such as perfluorocyclobutane,perfluoromethylcyclobutane, perfluorodimethylcyclobutanes,perfluorotrimethylcyclobutanes, perfluorocyclopentane,perfluoromethylcyclopentane, perfluorodimethylcyclopentanes,perfluorocyclohexane, perfluoromethylcyclohexane andperfluorocycloheptane; and mixtures of any of the foregoing, includingmixtures with gases such as nitrogen, carbon dioxide, oxygen etc, butnot limited to those.

In another embodiment, contrast in achieved using small organic iodinecontaining compounds. Said small organic iodine containing compoundsincludes commercial available iodinated contrast agents such asdiatrizoate (marketed e.g. under the trade name Gastrografen™), ionicdimers such as ioxaglate (marketed e.g. under the trade name Hexabrix™),nonionic monomers such as iohexol (marketed e.g. under the trade nameOmnipaque™), iopamidol (marketed e.g. under the trade name Isovue™)iomeprol (marketed e.g. under the trade name Iomeron™) and the non-ionicdimer iodixanol (marketed under the trade name and Visipaque™).Additional examples of small organic iodine containing compoundsincludes the ones disclosed in WO 2009/071605 , EP1186305, EP686046,EP108638, EP0049745, EP0023992, WO 2003080554, WO 2000026179, WO1997000240, WO 9208691, U.S. Pat. No.3,804,892, U.S. Pat. No.4,239,747,U.S. Pat. No.3,763,226, U.S. Pat. No.3,763,227 and U.S. Pat.No.3,678,152, but not limited to those. In another interestingembodiment, the said small organic iodine containing compounds includesiodinated derivates of sucrose acetate isobutyrate (SAIB). In contrastto what is disclosed in for example EP1006935, where a composition forcontrolled release of a substance is disclosed which compositioncomprises SAIB, this specific embodiment according to the presentinvention aims at providing a stable contrast agent embedded inSAIB-gel. Such compounds may be used alone or in combination with solidparticles to achieve an injectable gel visible by at least CT imaging.In one specific embodiment of the invention the hydration sensitive gelforming component is sucrose acetate isobutyrate (SAIB) a hydrophobiccomponent composed of sucrose (the scaffold), which has been acylatedwith isobutyrate and acetate. Preferred scaffolds of this invention aremonosaccharides, disaccharides or trisaccharides. A particularlypreferred dissacharide scaffold are sucrose and lactose, however, thealcohol containing scaffold may be derived from a polyhydroxy alcoholhaving from about 2 to about 20 hydroxy groups and may be formed byesterifying 1 to 20 polyol molecules. Suitable alcohol moieties includethose derived by removing one or more hydrogen atoms from:monofunctional C1-C20 alcohols, difunctional C1-C20 alcohols,trifunctional alcohols, hydroxy-containing carboxylic acids,hydroxy-containing amino acids, phosphate-containing alcohols,tetrafunctional alcohols, sugar alcohols, monosaccharides, anddisaccharides, sugar acids, and polyether polyols. More specifically,alcohol moieties may include one or more of: dodecanol, hexanediol, moreparticularly, 1,6-hexanediol, glycerol, glycolic acid, lactic acid,hydroxybutyric acid, hydroxyvaleric acid, hydroxycaproic acid, serine,ATP, pentaerythritol, mannitol, sorbitol, glucose, galactose, fructose,maltose, lactose, glucuronic acid, polyglycerol ethers containing from 1to about 10 glycerol units, polyethylene glycols containing 1 to about20 ethylene glycol units. Additionally, any oligosaccharide containingfrom 3 to about 6 monosaccharides may be used as the scaffold in thepresent invention. In general, the scaffold esters of the invention canbe made by reacting one or more alcohols, in particular one or morepolyols, which will form the alcohol moiety of the resulting esters withone or more carboxylic acids, lactones, lactams, carbonates, oranhydrides of the carboxylic acids which will form the acid moieties ofthe resulting esters. The esterification reaction can be conductedsimply by heating, although in some instances addition of a strong acidor strong base esterification catalyst may be used. Alternatively, anesterification catalyst such as stannous 2-ethylhexanoate or activationreagents such as N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC),N,N′-Dicyclohexylcarbodiimide (DCC),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and the like can be used.

The acyl groups forming the acyloxy substituents of the invention may beany moiety derived from a carboxylic acid. More particularly, the acylgroups of the compositions of the invention may be of the RCO—, where Ris optionally oxy-substituted alkyl of 2-10 carbon atoms which may belinear or branched hydrocarbons with one or more functional groupspresent in the chain. Using carboxylic acids and/or polyols of differentchain length and using carboxylic acids having oxy-substitution allowscontrol of the degree of hydrophilicity and of the solubility of theresulting ester. Such materials are sufficiently resistant todissolution in vivo that they are able to form stabile hydrophobic gelswhich may encapsulate the said contrast agents of the present invention.

In one embodiment the composition for use is an X-ray contrast agentcomprises one or more iodinated polymers, iodinated oligomers, iodinatedlipids, iodinated saccharides, iodinated disaccharides, iodinatedpolysaccharides, iodinated peptides, or a derivative or a combinationthereof. The composition for use according to any of the precedingclaims, wherein the composition comprises iodinated derivates ofcarbohydrate or iodinated derivative of poly-alcohols, such as iodinatedderivatives of sucrose acetate isobutyrate (SAIB), such as iodinatedderivatives of lactose, such as iodinated derivatives of trehalose, suchas iodinated derivatives of arabinose, such as iodinated derivatives ofmaltose, such as iodinated derivatives of glucose, such as iodinatedderivatives of galactose, iodinated derivatives of glucosamine, such asiodinated glucosamine, and the like. In yet another embodiment thecomposition comprises an iodinated derivate of a carbohydrate doped intoa composition of the same class of non-idoninated carbohydratederivatives.

Further, in one embodiment, the X-ray contrast composition comprisessucrose acetate isobutyrate (SAIB) or a derivative thereof and in onespecific embodiment of the present invention, the X-ray contrastcomposition comprises an iodinated derivate of sucrose acetateisobutyrate (SAIB). Furthermore in another specific embodiment of thepresent invention the X-ray contrast composition comprises an iodinatedderivate of sucrose acetate isobutyrate (SAIB) doped into sucroseacetate isobutyrate (SAIB). This has been evaluated for stability andthe amount of this iodo-SAIB/SAIB that can be doped into SAIB, is atleast 50 mol %.

The iodo-SAIB provides high X-ray contrast. The iodo-SAIB compound ispoorly soluble in ethanol and is a white solid whereas SAIB is highlysoluble in ethanol and is a thick oil. However, a mixture of ethanol andSAIB can solubilize the iodo-SAIB very nicely. This means that the SAIBhelps solubility of iodo-SAIB, which is an interesting feature and whichprovides an injectable solution which gelates after administration(through a thin needle, thinner than 20 gauge) that can function as ahigh contrast X-ray marker. When injected into mice, the iodo-SAIB/SAIBprovides high contrast and has the desirable stability properties.Furthermore, the gel seems homogeneous. In one embodiment of the presentinvention the X-ray contrast composition comprises an iodinated derivateof sucrose acetate isobutyrate (SAIB) solubilised in a mixture ofethanol and sucrose acetate isobutyrate (SAIB).

Features of Injectable Medical Gel-Forming System

(1) In order to be injectable, the system should be in a sol state suchas a liquid like state before administration. The sol state should be ofsufficiently low viscosity—typically lower than 10,000 cP, preferablylower than 2,000 cP, at 20° C. (or alternatively lower than lower than10,000 cP, preferably 2,000 cP, at 5° C.)—to allow for small needle headto alleviate the patient discomfort and simplify insertion procedure.

(2) Gelation via physical association or hydration starts to happen oris complete after injection.

(3) The gels should be biodegradable or gradually dissolvable within acontrolled time period, and the products should be cleared/secretedthrough normal pathways.

(4) The polymer itself and the degradable products should bebiocompatible. Likewise, if additives are added, such as cross-linkingagents, initiators etc. these should also be biocompatible.

(5) The gel could potentially have cell/tissue-adhesive properties.

It should be understood, that the gel-forming system should preferablybe biocompatible, i.e. does not stimulate a severe, long-lived orescalating biological response to the formulation when injected into amammal, in particular a human. To facilitate metabolism of the gelscaffold, degradable linkages can be included through the use ofpolylactide, polyglycolide, poly(lactide-co-glycolide), polyphosphazine,polyphosphate, polycarbonate, polyamino acid, polyanhydride, andpolyorthoester-based building blocks, among others. Additionally, smallmolecule crosslinking agents containing similar hydrolyzable moieties asthe polymers such as carbonates, esters, urethanes, orthoesters, amides,imides, imidoxy, hydrazides, thiocarbazides, and phosphates may be usedas building blocks. Additionally, polyglycolide diacrylate,polyorthoester diacrylate and acrylate-substituted polyphosphazine,acrylate-substituted polyamino acid, or acrylate-substitutedpolyphosphate polymers can be used as degradable building blocks.Methacrylate or acrylamide moieties can be employed instead of acrylatemoieties in the above examples. Similarly, small molecules containing ahydrolyzable segment and two or more acrylates, methacrylates, oracrylamides may be used. Such degradable polymers and small moleculebuilding blocks may be functionalized with acrylate, methacrylate,acrylamide or similar moieties by methods known in the art.

In order to be injectability, the system should be in a sol state beforeadministration. The sol state should be of sufficiently low viscosity toallow for small needle head to alleviate the patient discomfort andsimplify insertion procedure. Gelation via physical association startsto happen or is complete after injection.

In one embodiment, the composition according to the present invention isadministered using topical route.

In one embodiment, the composition according to the present invention isintra-cavitary administration into existing or established bodycavities. The existing cavities include, but are not limited to; urinarybladder, uterus, gall bladder, sinuses, middle ear. The established orformed cavities include, but are not limited to cavities formed inrelation to surgery and infections.

Viscosity of the Formulation

The viscosity of the formulation is before the injection preferablylower than 10,000 cP, in particular lower than 2,000 cP, at 20° C.Alternatively, the viscosity of the formulation is before the injectiontypically lower than 2,000 cP at 5° C.

In one embodiment, the gel-forming system of the formulation ispreferably one which, after injection or under conditions mimickingthose in a human body, forms a gel having a viscosity at 37° C. in therange of 2,000 to 50,000,000 cP. More particularly, the viscosity of thehydrogel can be about 2,000 cP, about 5,000 cP, about 10,000 cP, about20,000 cP, about 30,000 cP, about 50,000 cP, about 75,000 cP, about100,000 cP, about 125,000 cP, about 150,000 cP, about 200,000 cP, about30,000 cP, about 800,000 cP, about 1,000,000 cP, about 2,000,000 cP,about 5,000,000 cP, about 10,000,000 cP, about 20,000,000 cP, about30,000,000 cP, about 40,000,000 cP, about 50,000,000 cP, or rangesthereof. Preferably, the viscosity of the hydrogel after injection (i.e.when present in the desired location) is above 20,000 cP, e.g. in therange of 20,000 cP to 1,000,000 cP. In particular, the formulation afterinjection is preferably essentially solid.

Preferred Properties of the Gel-Forming System

In one embodiment, the preferred systems include non-water solublehigh-viscosity liquid carrier materials such as non-water solublecarbohydrates and in particular carbohydrates selected from derivativesof disaccharides with at least two pyranose saccharide units,trisaccharides, tetrasaccharides or mixtures thereof, or derivatives oflactose, maltose, trehalose, raffinose, glucosamine, galactosamine,lactosamine, or mixtures thereof. Such systems may be mixed with solidparticles that carry drug or contrast agent followed by parentalinjection, thus functioning as a injectable composition, which that canbe visualized by one or multiple imaging modalities, including X-rayimaging.

In one embodiment of the invention the composition comprising anon-water soluble carbohydrate, wherein the composition is a liquidbefore administration into the human or animal body and increases inviscosity by more than 1,000 centipoise (cP) after administration. Inone embodiment of the invention the composition comprising a non-watersoluble carbohydrate, wherein the composition is a liquid beforeadministration into the human or animal body and increases in viscosityby more than 10,000 centipoise (cP) after administration.

In one embodiment, at least 60% of an administrated amount of thenon-water soluble carbohydrate remains more than 24 hours within 10 cmfrom an injection point when administrated to a human or animal body.

In one preferred embodiment, the mixing of different acylatedcarbohydrates, results in controlled drug release providing tuning ofrelease kinetics for the individual drug. The composition according tothe present invention also relates to the release of one or more activepharmaceutical ingredients being controlled by mixing carbohydrates withdifferent hydrophobicity by alteration of the substitutions on thecarbohydrate hydroxyl groups. With the aid of tuning the hydrophobicity,the release rate of the present invention may be changed, this impliestherefore increased control of the process. Rendering it suitable forcontrolled release of for example pharmaceutuicals and other substances.Active pharmaceuticals may be formulated in various forms and thepresent invention is to be seen as incorporating various forms offormulations of the active ingredient.

Other Constituents of the Formulation

In one embodiment a polymer may be used to work as a stabilizer betweengel and biological surrounding and therefore, the composition may alsocomprises a molecule that increase gel stability in the human or animalbody, such as an amphiphilic molecule, such as an emulsifier. Thereforein one embodiment the composition comprises poly(ethyleneglycol-b-caprolactone) (PEG-PCL), sucrose acetate isobutyrate (SAIB),poly(D,L-lactic acid) (PLA), or poly(lactic-co-glycolic acid) (PGLA), ora combination thereof. In one embodiment of the present inventionpoly(D,L-lactic acid) (PLA) is added to the non-water solublecarbohydrate causing a reduction of burst release of said encapsulatedcontents e.g. drugs, particles, contrast agents, etc. The formulationmay further include other constituents, such as α-, β-, and/orγ-cyclodextrins and any derivate hereof. Such constituents may formguest/host complexes with the gel forming system and the nano-sizedparticles, thus, both aiding in the gel formation and possible alter theparticle leakage profile [Adv. Drug Delivery Rev., 2008, 60, 1000-1017].In one very interesting embodiment the gel forming system is based onPEG-PHB-PEG triblock copolymers, α-cyclodextrin and PEG coated solidnano sized particles. In such a formulation, α-cyclodextrin may forminclusion complexes with both the PEG blocks of the PEG-PHB-PEG triblockcopolymers and the PEG coated solid nano sized particles which, combinedwith hydrophobic interactions between the PHB middle block, forms astrong hydrogel with enhanced retention of solid nano sized particlesdue α-cyclodextrin interactions which thus altering the particle leakageprofile.

The formulation may further comprise compounds or polymers, which arevisible in imaging modalities other than X-ray imaging.

In one embodiment, the formulation further comprises aniodine-containing polymer, e.g. polyvinylpyrrolidone-iodine (PVP-I), orone selected from i) Polym. Chem., 2010, 1, 1467-1474,10 U.S. Pat. No.3,852,341, iii) U.S. Pat. No. 4,406,878, iv) U.S. Pat. No. 5,198,136, v)Biomedical polymers and polymers therapeutics, Ed. Chiellini E.,Sunamoto J., Migliaresi C., Ottenbrite R. M., Cohn D., New York, KluwerAcademic Publishers, 2002, ISBN 0-30646472-1, Print, and referencescited therein. Such polymers can be added to the gel forming componentsprior to gelation and function as contrast agent in vivo. Such polymersmay additionally or alternatively be covalently bound to the one or moreof the gel forming components or adhered to the particles of the presentinvention.

In one specific embodiment, the formulation consist of iodinated SAIB ascontrast agent with high HU-contrast or a iodinated carbohydrate.

Pharmaceutical Agent

The gel-forming formulation may further comprise pharmaceutical agentsincluding prodrugs (in short “drugs”; broadly interpreted as agentswhich are able to modulate the biological processes of a mammal). Thesedrugs can be formulated as a single drug or as a combination of two ormore of the below mentioned drugs in its active form or as a prodrug.

In one embodiment, the active pharmaceutical ingredient is animmunomodulating compound which is a ligand for intracellular proteinsand/or receptors; or a ligand for cell surface proteins and/orreceptors. In yet another embodiment, the intracellular proteins and/orreceptors are selected from the group consisting of NOD-like receptor(NLR) family and the subfamilies NLRA, NLRB, NLRC, NLRP, NODs, NALP,IPAF, HLA complexes, Receptor tyrosine kinases (RTK), Integrins, tumornecrosis factor receptor superfamily (TNFRSF; TNFR1, TNFR2, OX40, 4-1BB,CD40), ATP and ADP receptors; P2×1-7 and G-protein coupled P2Y₁₋₈,cyclo-oxygenase (COX) receptors, prostaglandin receptors, chemokinereceptors; CXCR and CCR, EIF2AK4, RIG-I-like receptors, cytokinereceptors, interleukin receptors, CD proteins, CTLA proteins, PD1, TCell receptor, B cell receptor, and the Toll-like-receptor (TLR) family;TLR1, TLR2 TLR3, TLR4, TLRS, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11,TLR12, TLR13.

Examples of pharmaceutical active agents include small drugs, plasmidDNA (e.g. for gene therapy), dsRNA, ssRNA, mRNA, siRNA, carbohydrates,peptides and proteins. Specific examples of pharmaceutical agentsinclude; a) chemotherapeutic agents such as alkylating agents,antimetabolites, enzymes (e.g. L-asparginase), natural productchemotherapeutics including tubulin stabilizing and destabilizingagents, hormones and antagonists, etc.; b) radiation sensitizing agentssuch as gemcitabine and doranidazole, porphyrins for photodynamictherapy (e.g. visudyne) or ¹⁰B clusters or ¹⁵⁷Gd for neutron capturetherapy; c) peptides or proteins that modulate apoptosis, the cellcycle, or other crucial signaling cascades; d) anti inflammatory drugs,such as methylprednisolone hemisuccinate, β-methasone; e) anti anxietymuscle relaxants such as diclofenac, pridinol; f) local anesthetics suchas lidocaine, bupivacaine, dibucaine, tetracaine, procaine; g)analgesics such as opiods, non-steroidal anti-inflammatory drugs(NSAIDs); h) antimicrobial medications such as pentamidine, azalides; i)antipsychotics such as chlorpromazine, perphenazine; j) theanti-parkinson agents such as budipine, prodipine, benztropine mesylate,trihexyphenidyl, L-DOPA, dopamine; k) Antiprotozoals such as quinacrine,chloroquine, amodiaquine, chloroguanide, primaquine, mefloquine,quinine; I) antihistamines such as diphenhydramine, promethazine; m)antidepressants such as serotonin, imipramine, amitriptyline, doxepin,desipramine; n) anti anaphylaxis agents such as epinephrine; o)anticholinergic drugs such as atropine, decyclomine, methixene,propantheline, physostigmine; p) antiarrhythmic agents such asquinidine, propranolol, timolol, pindolol; q) prostanoids such asprostaglandins, thromboxane, prostacyclin, but not limited to those; r)immunotherapeutic agents such as imidazoquinoline amine,immunomodulators, guanosine derivatives, pyrimidone derivatives,immunosuppressants, pro- or anti-inflammatory cytokines, antibodies, butnot limited to those.

Additional examples of antitumor agents and/or radiation sensitizingagents include camptothecin derivatives such as irinotecanhydrochloride, nogitecan hydrochloride, exatecan, RFS-2000, lurtotecan,BNP-1350, Bay-383441, PNU-166148, IDEC-132, BN-80915, DB-38, DB-81,DB-90, DB-91, CKD-620, T-0128, ST-1480, ST-1481, DRF-1042 and DE-310,taxane derivatives such as docetaxel hydrate, IND-5109, BMS-184476,BMS-188797, T-3782, TAX-1011, SB-RA-31012, SBT-1514 and DJ-927,ifosfamide, nimustine hydrochloride, carboquone, cyclophosphamide,dacarbazine, thiotepa, busulfan, melphalan, ranimustine, estramustinephosphate sodium, 6-mercaptopurine riboside, enocitabine, gemcitabinehydrochloride, carmofur, cytarabine, cytarabine ocphosphate, tegafur,doxifluridine, hydroxycarbamide, fluorouracil, methotrexate,mercaptopurine, fludarabine phosphate, actinomycin D, aclarubicinhydrochloride, idarubicin hydrochloride, epirubicin hydrochloride,daunorubicin hydrochloride, pirarubicin hydrochloride, bleomycinhydrochloride, zinostatin stimalamer, neocarzinostatin, mytomycin C,bleomycin sulfate, peplomycin sulfate, vinorelbine tartrate, vincristinesulfate, vindesine sulfate, vinblastine sulfate, amrubicinhydrochloride, gefitinib, exemestan, capecitabine, TNP-470, TAK-165,KW-2401, KW-2170, KW-2871, KT-5555, KT-8391, TZT-1027, S-3304, CS-682,YM-511, YM-598, TAT-59, TAS-101, TAS-102, TA-106, FK-228, FK-317, E7070,E7389, KRN-700, KRN-5500, J-107088, HMN-214, SM-11355, ZD-0473,magnesium 5,10,15,20-tetrakis(4-sulphophenyl)-porphine dodecahydrate,PYROA protein (Emericella nidulans), photosan III, lomefloxacin,cyamemazine, tiaprofenic acid, doxorubicin, mitomycin, paclitaxel,nitrogen mustards, etoposide, camptothecin, 5-fluorouracil,nicotinamide, metronidazole, doxorubicine, Lomeguatrib, Temozolomide,tamoxifen, bleomycin, 5-fluorouracil, cyclophosphamide, methotrexate,gemcitabine, oxaliplatin, cisplatin, carboplatin, camptothecin, CPT-11(SN-38), Etanidazole, Nimorazole, Mitomycin C, Tirapazamine, procaine,lidocaine, chlorpromazine, Fluordeoxyuridine, bromodeoxyuridine,iododeoxyuridine, hydroxyurea, fludarabine, Texaphyrins (motexafingadolinium), N-ethylmalemide, paclitaxel, docetaxel, irinotecan,Mechtorethamine, Cyclophosphamide, Ifosfamide, Melphalan, Chlorambucil,Procarbazine (N-methylhydrazine, MIH), Busulfan, Camustine (BCNU),Streptozocin (streptozotocin), Bendamustine, Dacarbazine (DTIC;dimethyttriazenol midazole carboxamide), Temozolomide, Cisplatin,carboplatin, oxaliplatin, Methotrexate (Amethopterin), Pemetrexed,Fluorouracil (5-fluorouracil; 5-FU), capecitabine, Cytarabine (cytosinearabinoside), Gemcitabine, 5-aza-cytidine, Deoxy-5-aza-cytidine,Mercaptoptirine (6-mercaptopurine; 6-MP), Pentostatin(2′-deoxycoformycin), camptothecin, SN-38 (CPT-11), Rudarabine,Clofarabine, Nelarabine, Tirapazamine, Vinblastine, Vinorelbine,Vincristine, Paclitaxel, docetaxel, Etoposide, Teniposide, Topotecan,Irinotecan, Dactinomycin, (actinomycin D). Daunorubicin (daunomycin,rubidomycin), Doxorubicin, Yondelis, Mitoxantrone, Bleomycin, MitomycinC, L-Asparaginase, Mitotane (o.pDDD) Prednisone, Hydroxyprogesteronecaproate, medroxyprogesterone acetate, megestrol acetate,Dietyhlstilbestrol, ethinyl estradiol, Tamoxifen, toremifene,Anastrozole, letrozole, exemestane, Testosterone propionate,fluoxymesterone, Flutamide, casodex, Leuprolide. Hydroxyurea, Tretinoin,arsenic trioxide, Histone deacetylase inhibitor (vorinostat), Imatinib,Dasatinib, nilotinib, Gefrtinib, ertoinib, Sorafenib, Sunitinib,Lapatinib, Bortezomib, interferon-alfa, Interleukin-2, interleukin-15,Thalidomide, Lenaiidomide, Temsiroiimus, Everolimus, and the like, butnot limited to those.

Examples of immunotherapeutic agents include resiquimod, imiquimod,thalidomide, lenalidomide and pomalidomide, sargramostim, IL-2, IL-15,IFN-a, IFN-b, IFN-g, interferon-alfa, alemtuzumab, bevacizumab,brentuximab vedotin, cetuximab, gemtuzumab, ozogamicin, ibritumomab,tiuxetan, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab,trastuzumab, loxoribine, bropirimine, pomalidomide, sargramostim and thelike, but not limited to those. In one embodiment, the activepharmaceutical ingredient is an immuno stimulating compound selectedfrom the group consisting of polyinosinic:polycytidylic acid (poly I:C),Polyadenylic-polyuridylic acid (poly A:U), poly I:C-poly-L-lysine(poly-ICLC), poly-ICR, 3p′dsRNA, 3p′dsDNA, 2p′dsRNA, 2p′dsDNA, p′dsRNA,p′dsDNA, dsRNA, dsDNA, ssDNA, ssRNA, methyl-tryptophan, D-1MT, L-1MT,tryptophan, INCB24360, NLG919, INCB24360 (Incyte), NLG919 (NewLinkGenetics), LM10 (Ludwig Institute), Compound 9 (The Institutes forPharamceutical Discovery), NCX-4016 (NicOx), AT38 (IRCCS), Tadalafil(Eli Lilly), arginine, N-hydroxy-nor-L-arginine, AZ10606120 (Universityof Ferrara), NF340 (Uni Dusseldorf), SCH58261 (Peter MacCallum CancerCentre), SCH420814 (Merck), PSB1115 (Uni Salerno), ARL67176 (OregaBiotech), AMPCP (Uni Texas San Anthonio), Celecoxib (Pfizer), PF04418948(Pfizer), RQ-15986 (RaQualia Pharma), Plerixafor (Sanofi-Avantis),PF-4136309 (Pfizer), Maraviroc, OM-174, 852A (Pfizer), VTX-2337(VentiRx), IM-2055 (Idera Pharmaceuticals), LY2157299 (Eli Lilly),EW-7197 (Ewha), BLZ945, BMS-777607, PI-3065, TG100-115, Babrafenib,Vemurafenib, ARL67176, VS4718, ASP3026, Crizotinib, GSK1838705,KRCA0008, PF064639229, CL264,N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-(R)-cysteine-(S)serine-(S)lysine4 (Pam₃Cys), Monophosphoryl lipid A (MPLA) and otherlipopolysaccharides, alpha-galactosylceramide, Propirimine, Imiquimod(R837), resiquimod (R848), TMX-101, TMX-201, TMX-202, Gardiquimod, R850(3M Pharma), R851 (3M Pharma), 852A (3M Pharma), S-27610, 3M-002(CL075), 3M-003, 3M-005, 3M-006, 3M-007, 3M-012, 3M-13, 3M-031,3M-854(3M Pharma), CL097, CL264, IC-31, Loxoribine and otherimidazoquinolines, ssPolyU, sotirimod (3M Pharma), Isatoribine (Anadys),ANA975 (Anadys/Novartis), SM360320 (Sumitomo), R1354 (ColeyPharmaceuticals) single stranded or double stranded RNA, ORN 02(5′-UUAUUAUUAUUAUUAUUAUU-3′), ORN 06 5′-UUGUUGUUGUUGUUGUUGUU-3′, CpG-ODNDSLIM (Mologen), AVE 0675 (Coley Pharmaceuticals), CpG Boligodeoxynucleotide (ODN) 1018 (Dynavax Technologies), AZD 1419(Dynavax), ODN 1982, CpG B ODN 2006 (Coley Pharmaceuticals), IMO 2125(Idera Pharma), CpG A ODN 2216, CpG A ODN 2336, CpG 2395, CpG ODN 7909(Coley Pharmaceuticals), CpG 10101 (Coley Pharmaceuticals), CpG ODNAVE0675 (Coley Pharmaceuticals), CpG ODN HYB2093 (IderaPharmaceuticals/Novartis), CpG ODN HYB2055 (Idera Pharmaceuticals),CpG-ODN IMO-2125 (Idera Pharmaceuticals), CpG C ODN M362, Tolamba (Amba1 ragweed allergen with covalently linked CpG B class ODN 1018)(DynavaxTechnologies), Heplisav (Dynavax Technologies), 10181SS (DynavaxTechnologies), IM02055 (Idera Pharmaceuticals), IRS954 (DynavaxTechnologies), (flagellin, muramyl dipeptide, saponins such as QS21,Leishmania elongation factor, SB-AS4, threonyl-muramyl dipeptide,L18-MDP, mifamurtid, A83-01, A4476, GW788383, LY364947, R268712, RepSox,SB431542, SB505124, SB525334, SD208, FAK inhibitor 14, PF431396,PF573228, Yll and OM-174. In yet another embodiment, the activepharmaceutical ingredient is an immuno suppressive compound comprising asteroid selected from the group consisting of 21-Acetoxyprefnenolone,Aalclometasone, Algestone, Amicinonide, Beclomethasone, Betamethasone,Betamethasone dipropionate, Betamethasone hemisuccinate, Budesonide,Chloroprednisone, Clobetasol, Blovetasone, Clocortolone, Cloprednol,Corticosterone, Cortisone, Cortivazol, Deflazacort, Desonide,Desoximethasone, dexamethason, Dexamethasone palmitate, Dexamethasonephosphate, Diflorasone, Diflucortolone, Difluprednate, Enoxolone,Fluazacort, Flucloronide, Flumethasone, Flunisolide, FluocinoloneAcetonide, Fludrocortisone, Fluocinonide, Fluocortin Butyl,Fluocortolone, Fluorometholone, Fluperolone, Fluprednidine,Fluprednisolone, Flurandrenolide, Formocortal, Halcinonide,Glucocorticoids, Halomethasone, Halopredone, Hydrocortamate,Hydrocortisone, Limethasone, Mazipredone, Medrysone, Meprednisone,Methyolprednisolone, Methyolprednisolone hemisuccinate, MometasoneFuroate, Paramethasone, Prednicarbate, Prednisolone, Prednisolonepalmitate, Prednisolone phosphate, Prednisone, Prednival, Prednylidene,Tixocortal, and Triamcinolone. In yet another embodiment, the activepharmaceutical ingredient is an immuno suppressive compound comprising asmall molecule inhibitor acting on intracellular targets selected fromthe group consisting of c-Fms, PDGFR□, Abl, PDGFR□, NFkB, IkB, JAK1,JAK2, JAK3, GSK3, p38 MAPK, JNK, KIT, EGFR, ERBB2, ERBB4, VEGFR1,VEGFR2, VEGFR3, FLT3, PKC□, RAF1, CDK1, CDK2, CDK4, NLRP3, IRF3, STAT1,STAT2, STAT3, STAT4, STATS, STATE, Hsp90, Hsp70, PI3K, mTOR, AKT,DNA-PK, ATM, AMPK, PDK-1, S6 kinase, RIP2, TRIF, MYD88, TAK1. In yetanother embodiment, the active pharmaceutical ingredient is an immunosuppressive compound comprising a small molecule inhibitor acting onintracellular targets selected from the group consisting ofindomethacin, CLI-095 (C15H17CIFNO4S, CAS#243984-11-4), Bayl1-7082(C10H9NO2S, CAS#19542-67-7), Triptolide (PG 490), CGP53716, SU9518,PD166326, Celastrol, Tripterin, BIRB-796 (Doramapimod), SB 203580,SB202190, VX-702, NVP-BEZ235, GDC-0980 (RG7422), Ridaforolimus(Deforolimus, AP23573), Nilotinib (Tasigna,AMN107), Sorafenib tosylate(Nexavar), Dasatinib (Sprycel, BMS-354825), MLN518 (CT53518), Vatalanib(PTK787/ZK222584), OSI-930, AZD2171, Pazopanib (Votrient), IPI-504(retaspimycin), Deforolimus (Ridaforolimus), GDC-0980 (RG7422,C₂₃H₃₀N₈O₃S, CAS#1032754-93-0), Palomid 529 (C₂₄H₂₂O₆ CAS#914913-88-5),Imatinib mesylate (Gleevec/Glivec), Everolimus (Afinitor, RAD001),Sirolimus (Rapamune, rapamycin), Temsirolimus (Torisel, CCI-779),Bortezomib (Velcade), Gefitinib (Iressa), Canertinib (CI-1033, CAS#267243-28-7, C₂₄H₂₅CIFN₅O₃), Erlotinib hydrochloride (Tarceva),Pelitinib (EKB-569) (C₂₄H₂₃CIFN₅O₂, CAS#257933-82-7), Vandetanib(Zactima, ZD6474, C₂₂H₂₄BrFN₄O₂, CAS No.: 443913-73-3), Sunitinib(Sutent, SU-11248, C₂₂H₂₇FN₄O₂.C₄H₆O₅, CAS No.: 341031-54-7), Tandutinib(MLN518), C₃₁H₄₂N₆O₄, CAS No.: 387867-13-2, Roscovitine (Seliciclib),C₁₉H₂₆N₆O, CAS No.: 186692-46-6. In yet another embodiment, the activepharmaceutical ingredient is an anti-infectious compound selected fromthe group consisting of Rifampicin, dideoxycytidine-5′-triphosphate,Clarithromycin, acyclovir, ciprofloxacin, fusidin, gentamicin,chloramphenicol, levofloxacin, oxytetracyclin, tobramycin,natriumcromoglicat, Amoxicillin, Ampicillin, Pivampicillin, Ertapenem,Meropenem, Doripenem, Cefotaxim, Ceftazidim, Ciprofloxacin,Valaciclovir, efavirenz, emtricitabin, tenofovirdisoproxil, Rilpivirine,penicillin, Trimethoprim-sulfamethoxazole, rifampicin, etambutol,isoniazid, pyrazinamide, voriconazole, amphotericin B, caspofungin,flucytosine, itraconazole, doxycyclin, sulfonamides, andsulfamethoxazole, vancomycin, polymyxin B, polymyxin E, Enoxacin,Norfloxacin, Ofloxacin Levofloxacin, Moxifloxacin, Nadifloxacin,Lomefloxacin, Fleroxacin, Gatifloxacin, Grepafloxacin, Pefloxacin,Sparfloxacin, Temafloxacin, Trovafloxacin, Danofloxacin, Enrofloxacin,Ibafloxacin, Marbofloxacin, Orbifloxacin.

The drugs are included in the composition in an amount sufficient toachieve a desired effect. The amount of drug or biologically activeagent incorporated into the composition depends upon the desired releaseprofile, the concentration of drug required for a biological effect, andthe desired period of release of the drug. The biologically activesubstance is typically present in the composition in the range fromabout 0.5 percent to about 20 percent by weight relative to the totalweight of the composition, and more typically, between approximately 1percent to about 15 percent by weight. Another preferred range is fromabout 2 percent to about 10 percent by weight. For very active agents,such as growth factors, preferred ranges are less than 1% by weight, andless than 0.0001%.

Use of the Formulation as a Tissue Sealant

The present invention also provides the formulation as definedhereinabove for use as a tissue sealant, e.g. for needle canals formedby biopsy in conjunction with an imaging procedure according to theinvention.

The tissue sealant may include an effective amount of a hemostaticagent, e.g. an agent selected from coagulation factors, coagulationinitiators, platelet activators, vasoconstrictors and fibrinolysisinhibitors, e.g. epinephrine, adrenochrome, collagens, thrombin, fibrin,fibrinogen, oxidized cellulose and chitosan.

Specific Embodiments of the Invention as an X-Ray Contrast Composition

The present invention is in one embodiment an X-ray contrast compositionfor local administration, wherein the X-ray contrast compositionexhibits contrast properties and wherein at least 60% of anadministrated amount of said X-ray contrast composition remains morethan 24 hours within 10 cm from an injection point when the X-raycontrast composition is administrated to a human or animal body. Thereare of course various forms of injection patterns possible and ways ofinjecting, such as, but not limited to, transcutane injection, using ascope (bronchoscope, gastroscope, or any other flexible wired systemsused to navigate inside a body), attached to another such system,intracranial injection, inside air and fluent filled organs or cavities(e.g. bladder, stomach).

Further, there are various forms of dosing such as, but not limited to,fast injections (‘bolus’), pulling back to needle while injecting,slowly injection on the site, pushing the needle forward, and pumpgiving a constant pressure for a defined period. Furthermore, there arevarious devices that may be used such as, but not limited to, needlewith 1 or more holes on the side of the needle forming multiple smallerobjects, flexible, multiple chamber systems.

In one embodiment, the present invention has gelating properties and isa liquid before administration and has the ability to transform into agel after administration. In one specific embodiment, the presentinvention has gelating properties and is a homogeneous liquid beforeadministration and has the ability to transform into a gel afteradministration. Furthermore, in one embodiment the present invention isa non-colloidal x-ray contrast agent as part of a homogeneous liquidx-ray contrast composition that gels upon injection into a human oranimal subject. In yet another specific embodiment the X-ray contrastcomposition is a liquid before administration into a human or animalbody that increases in viscosity by more than 10,000 centipoise (cP)after administration into a human or animal body. In another specificembodiment the present invention has a viscosity of less than 10,000centipoise (cP) at 20° C.

Furthermore, from one perspective, the present invention, the X-raycontrast composition comprises an X-ray contrast agent that is part ofthe X-ray contrast composition and said X-ray contrast agent is anorganic substance.

It is the organic substance that is being the contrast “agent” and inone specific embodiment the X-ray contrast composition comprisesalginate and chitosan. In another specific embodiment the X-ray contrastagent comprises one or more natural polymers, synthetic polymers,oligomers, lipids, saccharides, disaccharides, polysaccharides, peptidesor any combination thereof and as mentioned before these may be thecontrast “agent”. In yet another specific embodiment of the presentinvention the X-ray contrast agent comprises one or more iodinatedpolymers, oligomers, lipids, saccharides, disaccharides,polysaccharides, peptides, or a derivative or a combination thereof.Further, in one embodiment the X-ray contrast agent is an inorganic acidor salt, such as chloroauric acid.

The present invention may in one embodiment comprise particles forvarious purposes. One purpose may be an additive contrast effect;another purpose may be to potentiating the effect and a third purposemay be as a carrier of e.g. medication or other substances. According toone specific embodiment of the present invention, the X-ray contrastcomposition comprises nanoparticles comprising gold (Au). In yet anotherembodiment the X-ray contrast composition also comprises particles inthe size range from 1-1000 nm, such as nanoparticles in the size rangefrom 2 to 500 nm and in one specific embodiment the nanoparticlescomprises gold (Au) which furthermore is the most likely substance. Inyet another embodiment, the X-ray contrast composition comprisingnanoparticle that may be an MRI, PET, ultrasound, fluorescence,radiofrequency, visible light contrast agent. Furthermore, in onespecific embodiment the nanoparticle is an MRI or PET contrast agent ora combination of the above mentioned imaging modalities.

As mentioned previously the present invention may have gelatingproperties and the gelling may be initiated by various factors such as,but not limited to, temperature, hydration, enzymatic activation, ionconcentration and/or pH. In one embodiment the X-ray contrastcomposition exhibits gel-formation in response to a temperature in therange of 35 to 40° C. In another embodiment the X-ray contrastcomposition exhibits gel-formation in response to hydration. In yetanother embodiment the X-ray contrast composition exhibits gel-formationin response to an ion-concentration in the range of 1 μM to 500 mM, suchas in the range of 1 mM to 200 mM. In one embodiment the ions aredivalent ions, such as calcium ions. In one embodiment the X-raycontrast composition exhibits gel-formation in response to a pH in therange of 6 to 8. In yet another embodiment, the X-ray contrastcomposition exhibits gel-formation in response to contacting with aninitiator and here an initiator can be many different things such as,but not limited to, ions, or a chemical reactive compound that crosslink other molecules.

In one embodiment, the X-ray contrast composition according to thepresent invention may comprise radioactive compounds, paramagneticcompounds, fluorescent compounds or ferromagnetic compounds, or anymixture thereof.

As mentioned previously, the X-ray contrast composition may also act asa carrier of substances such as, but not limited to, pharmaceuticalsubstances. The substance may be in the composition or in orcoated/linked to the nanoparticles. The substance may also be othertypes of additives. Examples of substance could be, but is not limitedto, substances suitable for chemotherapy, gemcitabine, cisplatin,doxorubicin, doranidazole, hormones or anti-bodies. In one embodimentthe X-ray composition comprise at least one pharmaceutical substance. Inone specific embodiment the X-ray contrast composition comprisesparticles in the size range from 1-1000 nm, such as nanoparticles in thesize range from 2 to 500 nm and wherein the particle contains at leastone pharmaceutical substance.

In one embodiment a polymer may be used to work as a stabilizer betweengel and biological surrounding and therefore, the X-ray contrastcomposition may also comprises a molecule that increase gel stability inthe human or animal body, such as an amphiphilic molecule, such as anemulsifier. Therefore in one embodiment the X-ray contrast compositioncomprises poly(ethylene glycol-b-caprolactone) (PEG-PCL), sucroseacetate isobutyrate (SAIB), poly(D,L-lactic acid) (PLA), orpoly(lactic-co-glycolic acid) (PGLA), or a combination thereof. In oneembodiment of the present invention poly(D,L-lactic acid) (PLA) is addedto sucrose acetate isobutyrate (SAIB) gel causing a reduction of burstrelease of said encapsulated contents e.g. particles drugs etc. Further,in one embodiment, the X-ray contrast composition comprises sucroseacetate isobutyrate (SAIB) or a derivative thereof and in one specificembodiment of the present invention, the X-ray contrast compositioncomprises an iodinated derivate of sucrose acetate isobutyrate (SAIB).Furthermore in another specific embodiment of the present invention theX-ray contrast composition comprises an iodinated derivate of sucroseacetate isobutyrate (SAIB) doped into sucrose acetate isobutyrate(SAIB). This has been evaluated for stability and the amount of thisiodo-SAIB/SAIB that can be doped into SAIB, is at least 50 mol %.

The iodo-SAIB provides high X-ray contrast. The iodo-SAIB compound ispoorly soluble in ethanol and is a white solid whereas SAIB is highlysoluble in ethanol and is a thick oil. However, a mixture of ethanol andSAIB can solubilize the iodo-SAIB very nicely. This means that the SAIBhelps solubility of iodo-SAIB, which is an interesting feature and whichprovides an injectable solution which gelates after administration(through a thin needle, thinner than 20 gauge) that can function as ahigh contrast X-ray marker. When injected into mice, the iodo-SAIB/SAIBprovides high contrast and has the desirable stability properties.Furthermore, the gel seems homogeneous. In one embodiment of the presentinvention the X-ray contrast composition comprises an iodinated derivateof sucrose acetate isobutyrate (SAIB) solubilised in a mixture ofethanol and sucrose acetate isobutyrate (SAIB).

One way of containing and also storing the composition may be, held inthe interior of a syringe. This indicates a possible shelf-life of atleast 6 months. One embodiment of the present invention is a kitcomprising a syringe, a hypodermal needle adapted to the open end ofsaid syringe, and a composition according to any one of the precedingclaims.

The intended use of the present invention is for radio therapy orimage-guided radio therapy, but not exclusively, other uses arethinkable such as, but not limited to, 2D X-ray scans, for use inimaging, diagnostics, treatment and/or quality rating of radio therapy.The present invention may be used as a tissue marker and/or for use as acontrolled drug release composition.

In one embodiment the X-ray contrast composition according to thepresent invention is for use in administration of an amount of 0.01-5.0mL and in one specific embodiment the X-ray contrast composition is foruse in administration wherein the amount is 0.1-1.0 mL. In oneembodiment the present invention may be used as a tissue sealant.

Methods for Treatment of Cancer

In one embodiment, the present invention relates to treatment ofcancerous diseases associated with malignant neoplasia such as malignantneoplasm of lip, mouth or throat, such as malignant neoplasm of thetongue, the base of tongue, gum, floor of mouth, palate, parotid gland,major salivary glands, tonsil, oropharynx, nasopharynx, piriform sinus,hypopharynx or other parts of lip, mouth or throat or malignantneoplasms of digestive organs such as malignant neoplasms of oesophagus,stomach, small intestine, colon, rectosigmoid junction, rectum, anus andanal canal, liver and intrahepatic bile ducts, gallbladder, other partsof biliary tract, pancreas and spleen, malignant neoplasms ofrespiratory and intrathoracic organs such as malignant neoplasms of thenasal cavity and middle ear, accessory sinuses, larynx, trachea,bronchus and lung, thymus, heart, mediastinum and pleura, malignantneoplasms of bone and articular cartilage such as malignant neoplasm ofbone and articular cartilage of limbs, bone and articular cartilage,malignant melanoma of skin, sebaceous glands and sweat glands, malignantneoplasms of mesothelial and soft tissue such as malignant neoplasm ofmesothelioma, Kaposi's sarcoma, malignant neoplasm of peripheral nervesand autonomic nervous system, malignant neoplasm of retroperitoneum andperitoneum, malignant neoplasm of connective and soft tissue such asblood vessels, bursa, cartilage, fascia, fat, ligament, lymphaticvessel, muscle, synovia, tendon, head, face and neck, abdomen, pelvis oroverlapping lesions of connective and soft tissue, malignant neoplasm ofbreast or female genital organs such as malignant neoplasms of vulva,vagina, cervix uteri, corpus uteri, uterus, ovary, Fallopian tube,placenta or malignant neoplasms of male genital organs such as malignantneoplasms of penis, prostate, testis, malignant neoplasms of the urinarytract, such as malignant neoplasms of kidney, renal pelvis, ureter,bladder, urethra or other urinary organs, malignant neoplasms of eye,brain and other parts of central nervous system such as malignantneoplasm of eye and adnexa, meninges, brain, spinal cord, cranial nervesand other parts of central nervous system, malignant neoplasms ofthyroid and other endocrine glands such as malignant neoplasm of thethyroid gland, adrenal gland, parathyroid gland, pituitary gland,craniopharyngeal duct, pineal gland, carotid body, aortic body and otherparaganglia, malignant neoplasms of head, face and neck, thorax, abdomenand pelvis, secondary malignant neoplasm of lymph nodes, respiratory anddigestive organs, kidney and renal pelvis, bladder and other and urinaryorgans, secondary malignant neoplasms of skin, brain, cerebral meninges,or other parts of nervous system, bone and bone marrow, ovary, adrenalgland, malignant neoplasms of lymphoid, haematopoietic and relatedtissue such as Hodgkin's disease, follicular non-Hodgkin's lymphoma,diffuse non-Hodgkin's lymphoma, peripheral and cutaneous T-celllymphomas, non-Hodgkin's lymphoma, lymphosarcoma, malignantimmunoproliferative diseases such as Waldenstrom's macroglobulinaemia,alpha heavy chain disease, gamma heavy chain disease,immunoproliferative small intestinal disease, multiple myeloma andmalignant plasma cell neoplasms such as plasma cell leukaemia,plasmacytoma, solitary myeloma, lymphoid leukaemia such as acutelymphoblastic leukaemia, myeloid leukaemia, monocytic leukaemia, blastcell leukaemia, stem cell leukaemia, and other and unspecified malignantneoplasms of lymphoid, haematopoietic and related tissue such asLetterer-Siwe disease, malignant histiocytosis, malignant mast celltumour, true histiocytic lymphoma or other types of malignant neoplasia.

According to the present invention, treatment of carcinoma in situ oforal cavity, oesophagus, stomach, digestive organs, middle ear andrespiratory system, melanoma in situ, carcinoma in situ of skin,carcinoma in situ of breast, carcinoma in situ of female or malegenitals, carcinoma in situ of bladder, urinary organs or eye, thyroidand other endocrine glands, or other types of carcinoma in situ.

Specific Embodiments of the Invention for use in HIFU/Proton Therapy:

Advances in modern radiation techniques have enabled increasinglyconformal radiotherapy from three-dimensional conformal radiotherapy tointensity modulated radiotherapy (IMRT) and proton therapy. Thesetechniques minimizes dose to organs at risk and may enable doseescalation. Dose escalation prerequisites accurate and reproduciblepatient positioning and target alignment as poor targeting accuracy maycompromise local tumor control and increase the risk of radiationinduced toxicity.

In image-guided radiation therapy (IGRT) with 2D-(kV-radiographs) or 3Dx-ray (cone beam computed tomography (CT)) images are recorded beforeand sometimes during treatment. Alignments to bony anatomy or softtissue are used depending on the anatomical characteristics of thetarget. In some clinical cases the target position does not correlatewell with neither bony nor soft tissue anatomy, e.g. prostate cancer andlung tumors adjacent to the mediastinum. In these cases targetlocalization can be enhanced by alignment to radiopaque fiducial markersimplanted in or near the target.

Fiducial markers are routinely being used in connection with photonradiotherapy. However, use of fiducial markers in proton radiotherapyhas been approached with care as their presence can cause extremeperturbations in the therapeutic proton dose, which translates intosignificant colds spots downstream from the fiducial marker.

Perturbations in the proton beam for a variety of solid fiducial markersof different material have been investigated showing dose perturbationsup to 80% of the prescribed dose (4-10) ENREF 2 ENREF 2. Generally,small markers composed of low Z-materials yields the lowest doseperturbation. However, clinical relevant dose perturbation has beenreported for solid markers less than one millimeter in size.Consequently, both the actual marker size and position must be correctlyaccounted for in the proton treatment planning system, especially if themarker is located inside the treatment field.

The ideal fiducial marker for proton therapy is visible in CT- or kVimaging, causes no dose perturbation in a proton beam and do not induceimage artifacts on the CT-images used for treatment planning. Liquidmarkers have properties that are promising in this regard. A liquidmarker is a radiopaque fluid that is injected into the tissue. In oneembodiment the present invention is a composition wherein thecomposition is a fiducial marker for proton therapy. In anotherembodiment the present invention is a composition further comprising acontrast agent that makes the composition visible by CT or kV imaging.

High intensity focused ultrasound (HIFU, or sometimes MRgFUS formagnetic resonance guided focused ultrasound) is a medical procedurethat applies high intensity focused ultrasound energy to locally heatand destroy diseased or damaged tissue through ablation.

HIFU is a hyperthermia therapy, a class of clinical therapies that usetemperature to treat diseases. HIFU is also one modality of therapeuticultrasound, involving minimally invasive or non-invasive methods todirect acoustic energy into the body. In addition to HIFU, othermodalities include ultrasound-assisted drug delivery, ultrasoundhemostasis, ultrasound lithotripsy, and ultrasound-assistedthrombolysis.

Clinical HIFU procedures are typically performed in conjunction with animaging procedure to enable treatment planning and targeting beforeapplying a therapeutic or ablative levels of ultrasound energy. WhenMagnetic Resonance Imaging (MRI) is used for guidance, the technique issometimes called Magnetic Resonance guided Focused Ultrasound, oftenshortened to MRgFUS or MRgHIFU.

In one embodiment the present invention is a composition wherein thecomposition comprises contrast agents that makes the composition visibleby High intensity focused ultrasound (HIFU). In another embodiment ofthe invention the composition comprises agents that enhance thetherapeutic effect of HIFU when HIFU is used to treat diseased tissue.

Specific Embodiments of the Invention for use in PET Imaging:

Positron emission tomography (PET) is a modern and powerful technologyto study non-invasively biological processes at the molecular level.This highly sophisticated imaging method relies on coincidenceregistration of annihilation photons having a characteristic energy of511 keV. There is a wide range of positron-emitting halogens available;¹⁸F, ⁷⁵Br, ⁷⁶Br, and ¹²⁴1 which have been reported to be useful forapplications in oncology—with ¹⁸F as the most prominent among them.Generally, the decay of ⁷⁵Br, ⁷⁶Br, and ¹²⁴1 results in positrons ofhigher energy compared with ¹⁸F. This means a loss in spatial resolutionsince the positrons take a longer distance in tissue until annihilation.These alternative radiohalogens also emit y-rays of high energyresulting from electron capture (⁷⁵Br, ⁷⁶Br, ¹²⁴I) and internaltransitions (¹²⁴I).Table 1 compares some selected physical properties ofthese radioisotopes.

TABLE 1 Physical properties of isotopes used in PET-imaging. Ratio γenergy Effective dose Radio of β⁺ per decay constant nuclide t_(1/2) (%)E (β⁺ max) (MeV) (μSv/MBq h) ¹⁸F 110 in 97 0.635 — 5.37 ⁷⁵Br 97 min 911.74 0.473 7.85 ⁷⁶Br 16.2 h 54 3.98, 3.44, 2.226 12.5 ¹²⁴I 4.15 days 232.13, 1.53, 0.852 4.91 0.808 18F can be produced using three differentnuclear reactions, shown in Table 2. However, in practice only the²⁰Ne(d,α) and ¹⁸O(p,n) processes are relevant. Because of its hightarget yield the ¹⁸O(p,n) route has become the favored reaction.No-carrier-added (n.c.a.) ¹⁸F is obtained from proton irradiation of¹⁸O-enriched medium.

TABLE 2 Production routes for ¹⁸F Energy range Theoretical thick targetyield Nuclear reaction (MeV) (MBq/μAh) ²⁰Ne(d,α)¹⁸F 14→0 1110¹⁸O(p,n)¹⁸F 16→3 2960 ¹⁶O(³He,p)¹⁸F  41→14 481PET-Imaging in Connection with Proton Therapy:

Positron emission tomography (PET) is potentially a very useful tool formonitoring the distribution of the dose deposited in the patient fromproton therapy. This method is based on the detection of thepositron-annihilation γ-rays following the decay of the small amounts ofpositron emitters (typically ¹¹C (t½=20.39 min), ¹³N (t½=9.96 min) and¹⁵O (t½=2.04 min)) produced via non-elastic nuclear reaction of protonswith the target nuclei of the irradiated tissue. Verification of thetherapy can be achieved by comparing the PET images discerning thepositron activity distribution with the predicted target dosedistribution used to plan the treatment. The expected number of nuclearreactions is governed by three factors: nuclear reaction cross sections,the number of incoming particles limited by target dose, and the numberof target particles.

Using isotopes produced during normal proton irradiation of soft tissuein problematic due to the short half-life of the ¹¹C, ¹³N and ¹⁵O (FIG.1), which often requires in-beam PET scanner and complex data analysisfollowing data accusation. Furthermore, using natural isotopes ischallenged by biological wash-out from proton irradiation to PET-imagingincreasing the uncertainty of the measurements.

Accurate estimation of the Bragg-peak-distal-edge (BPDE) location iscrucial in proton therapy dose delivery in order to verify thatundershooting and overshooting is not introduced due to change inpatient anatomy, motion etc. Current range verification techniquesincludes PET imaging which takes advantage of the β⁺ emitters producedfollowing proton interaction within the patient body. However, suchinteractions produce negligible PET signal at the BPDE due largely tothe decrease in proton energy with depth, which reduces the efficiencyof β⁺ emitter production.

Inclusion of ¹⁸O the present invention that is as a component in anycomposition described as well as sucrose based compositions andBioXmark™ as [18O]₆-sucrose octaacetate, or derivatives hereoffacilitates the ¹⁸O(p,n)¹⁸F nuclear reaction in vivo resulting information of ¹⁸F which can be detected using PET-imaging. The¹⁸O(p,n)¹⁸F reaction benefits from having a low interaction energythreshold which enables monitoring of small proton doses, givingpossibilities for radiation dose evaluation. Furthermore, the formed ¹⁸Fhas a sufficient half-life for patient monitoring.

A marker, which does not introduce dose perturbation in proton beams, isclearly visible for patient alignment/motion management and at the sametime can provide dosimetric output regarding the BPDE would be highlybeneficial for the proton community.

In one embodiment the present invention is a composition wherein thecomposition comprises contrast agents that makes the composition visibleby PET. In another embodiment the present invention is a compositionfurther comprising ¹⁸O.

A Kit Comprising the Formulation

The present invention further comprises a kit comprising a syringe, ahypodermal needle adapted to the open end of said syringe, and aformulation as defined hereinabove. In one embodiment, the formulationis held in the interior or said syringe.

The gel forming system may be provided as a lyophilized powder, asuspension or a solution. Different components may be provided in one ormore individual vials or pre-mixed in the interior or said syringe.Exemplary different components include, but are not limited to, thegel-forming system and the solid particles, and the formulation and oneor more initiators.

The syringe may consist of a single, a multiple barrel syringe (e.g.MEDMIX SYSTEMS AG) or a double champer syringe (e.g. Debiotech S.A.) andthe like, but not limited to those. Multiple barrel syringes and doublechamper syringes and the like may be useful for e.g. two componentsformulations were one component is a mixture of the gel forming system,the active pharmaceutical ingredient and potentially a contrast agent(s)and the other component is an initiator or salt suspension. In anotherembodiment a double chamber syringe may be useful where one chambercontains gel-forming component and the contrast agent(s) and the otherchamber the active pharmaceutical ingredient(s).

The needle of the syringe can, in some embodiments, be one suitable forfine-needle biopsies. Non-limiting examples of syringes and needles forsuch embodiments are described in U.S. Patent No. 7,871,383, U.S. patentpublication No. 20040162505, and references cited therein. Such syringesand needles can advantageously be used in procedures where a biopsy of atissue is to be taken in conjunction with imaging of the same, using aformulation of the invention. Preferably, the kit has a shelf-life of atleast 6 months, such as at least 12 months when stored at, e.g., roomtemperature (typically 18 to 25° C.) or lower temperatures, such as,e.g., 2 to 10° C., such as about 5° C. The shelf-life can, for example,be determined as the period wherein the kit can be stored at 25° C., at80% RH and 1 atm. pressure, and where the viscosity is kept within ±5%of the initial viscosity.

Structures

In a particular embodiment, the invention includes compositions whereinthe gel has a structure selected from the group consisting of:

Monosaccaharides: D-Glucosamine Derivatives:

wherein R₁, R₂, R₃, R₄ and R₅ are selected collectively from the groupconsisting of hydrogen, alkanoyl, hydroxyl-substituted alkanoyl, andacyloxy-substituted alkanoyl, alkanyl, hydroxysubstituted alkanyl andacyloxy substituted alkanyl; or wherein R₁, R₂, R₃, R₄ and R₅ areindependently selected from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl,carbohydrates and carbohydrate derivatives;

wherein all groups of R₁, R₂, R₃, R₄ and R₅ are selected collectivelyfrom the group consisting of acetyl, isobutyryl or propionyl; or whereinR₁, R₂, R₃, R₄ and R₅ are independently selected from the groupconsisting acetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

Disaccharides:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selected collectivelyfrom the group consisting of hydrogen, alkanoyl, hydroxyl-substitutedalkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstitutedalkanyl and acyloxy substituted alkanyl; or wherein R₁, R₂, R₃, R₄, R₅,R₆, R₇, and R₈ are independently selected from the group consisting ofhydrogen, alkanoyl, hydroxyl-substituted alkanoyl, andacyloxy-substituted alkanoyl, alkanyl, hydroxysubstituted alkanyl andacyloxy substituted alkanyl;

wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selectedcollectively from the group consisting of acetyl, isobutyryl orpropionyl; or

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selectedfrom the group consisting acetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

Lactose Derivatives:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selected collectivelyfrom the group consisting of hydrogen, alkanoyl, hydroxyl-substitutedalkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstitutedalkanyl and acyloxy substituted alkanyl; or wherein R₁, R₂, R₃, R₄, R₅,R₆, R₇, and R₈ are independently selected from the group consisting ofhydrogen, alkanoyl, hydroxyl-substituted alkanoyl, andacyloxy-substituted alkanoyl, alkanyl, hydroxysubstituted alkanyl andacyloxy substituted alkanyl;

wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selectedcollectively from the group consisting of acetyl, isobutyryl orpropionyl; or

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selectedfrom the group consisting acetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

Trehalose Derivatives:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selected collectivelyfrom the group consisting of hydrogen, alkanoyl, hydroxyl-substitutedalkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstitutedalkanyl and acyloxy substituted alkanyl; or wherein R₁, R₂, R₃, R₄, R₅,R₆, R₇, and R₈ are independently selected from the group consisting ofhydrogen, alkanoyl, hydroxyl-substituted alkanoyl, andacyloxy-substituted alkanoyl, alkanyl, hydroxysubstituted alkanyl andacyloxy substituted alkanyl;

wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selectedcollectively from the group consisting of acetyl, isobutyryl orpropionyl; or

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selectedfrom the group consisting acetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

Maltose Derivatives:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selected collectivelyfrom the group consisting of hydrogen, alkanoyl, hydroxyl-substitutedalkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstitutedalkanyl and acyloxy substituted alkanyl; or wherein R₁, R₂, R₃, R₄, R₅,R₆, R₇, and R₈ are independently selected from the group consisting ofhydrogen, alkanoyl, hydroxyl-substituted alkanoyl, andacyloxy-substituted alkanoyl, alkanyl, hydroxysubstituted alkanyl andacyloxy substituted alkanyl;

wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selectedcollectively from the group consisting of acetyl, isobutyryl orpropionyl; or

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selectedfrom the group consisting acetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

Trisaccharides:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selectedcollectively from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; orwherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ areindependently selected from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl;

wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁are selected collectively from the group consisting of acetyl,isobutyryl or propionyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉,R₁₀ and R₁₁ are independently selected from the group consisting acetyl,isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ are selectedcollectively from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; orwherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ are independentlyselected from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl;

wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ areselected collectively from the group consisting of acetyl, isobutyryl orpropionyl; or

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ are independentlyselected from the group consisting acetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ areselected collectively from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; orwherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ areindependently selected from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl;

wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ andR₁₂ are selected collectively from the group consisting of acetyl,isobutyryl or propionyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉,R₁₀, R₁₁ and R₁₂ are independently selected from the group consistingacetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

Raffinose Derivatives:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selectedcollectively from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; orwherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ areindependently selected from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl;

wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁are selected collectively from the group consisting of acetyl,isobutyryl or propionyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉,R₁₀ and R₁₁ are independently selected from the group consisting acetyl,isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

Specific Embodiments of the Invention

One embodiment of the present invention relates to a compositioncomprising non-water soluble carbohydrates, wherein at least 50% of thenon-water soluble carbohydrates are carbohydrates selected fromderivatives of lactose, maltose, trehalose, raffinose, glucosamine,galactosamine, lactosamine, or derivatives of disaccharides with atleast two pyranose saccharide units, trisaccharides, tetrasaccharides,or mixtures thereof, and wherein the composition is a liquid beforeadministration into the human or animal body and increases in viscosityby more than 1,000 centipoise (cP) after administration, for use as amedicament. Another embodiment relates to a composition for use as acontrolled release system of one or more active pharmaceuticalingredients in a human or animal body. One embodiment relates to acomposition for use as a controlled release system, wherein thecomposition is a liquid before administration into the human or animalbody that increases in viscosity by more than 10,000 centipoise (cP)after administration into the human or animal body. One embodimentrelates to a composition for use as a controlled release system, whereinthe composition is a liquid before administration and has the ability totransform into a gel-like material after administration. One embodimentrelates to a composition for use as a controlled release system, whereinthe composition becomes a solid after administration, such as acrystalline or amorphous solid. One embodiment relates to a compositionfor use as a controlled release system, wherein an increase in viscosityafter administration into the human or animal body is due to diffusionof a molecule out of the administered material and into surroundingtissue. One embodiment relates to a composition for use as a controlledrelease system, wherein an increase in viscosity after administrationinto the human or animal body is due to diffusion of solvent-likemolecules. One embodiment relates to a composition for use as acontrolled release system, wherein the non-water soluble carbohydratesare disaccharides with structures selected from:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ in formulae I, II and III areselected collectively from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; orwherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selectedfrom the group consisting of hydrogen, alkanoyl, hydroxyl-substitutedalkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstitutedalkanyl and acyloxy substituted alkanyl;

or wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selectedcollectively from the group consisting of acetyl, isobutyryl orpropionyl; or

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selectedfrom the group consisting acetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

One embodiment relates to a composition for use as a controlled releasesystem, wherein the non-water soluble carbohydrates are trisaccharideswith structures selected from:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ in formulae IVare selected collectively from the group consisting of hydrogen,alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substitutedalkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substitutedalkanyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ areindependently selected from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl;

or wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁are selected collectively from the group consisting of acetyl,isobutyryl or propionyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉,R₁₀ and R₁₁ are independently selected from the group consisting acetyl,isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

One embodiment relates to a composition for use as a controlled releasesystem, wherein at least 50% of the non-water soluble carbohydrates aremono- or oligosaccharides containing at least one amino sugar unit. Oneembodiment relates to a composition for use as a controlled releasesystem, wherein the amino sugar has the structure:

wherein R₁, R₂, R₃, R₄ and R₅ in formulae V are selected collectivelyfrom the group consisting of hydrogen, alkanoyl, hydroxyl-substitutedalkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstitutedalkanyl and acyloxy substituted alkanyl; or wherein R₁, R₂, R₃, R₄ andR₅ are independently selected from the group consisting of hydrogen,alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substitutedalkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substitutedalkanyl, and mono-, di-, tri- or tetra-saccharide derivatives;

or wherein all groups of R₁, R₂, R₃, R₄ and R₅ are selected collectivelyfrom the group consisting of acetyl, isobutyryl or propionyl; or whereinR₁, R₂, R₃, R₄ and R₅ are independently selected from the groupconsisting acetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of anomers such as α- andβ-anomer centres of the above mentioned structural variations areclaimed.

One embodiment relates to a composition for use as a controlled releasesystem, wherein the release of one or more active pharmaceuticalingredients is controlled by mixing non-water soluble carbohydrates withdifferent hydrophobicity by alteration of the substitutions on thecarbohydrate hydroxyl groups. One embodiment relates to a compositionfor use as a controlled release system, wherein the activepharmaceutical ingredient is selected from a protein, a peptide, anucleoprotein, a mucoprotein, a lipoprotein, or a synthetic polypeptide.One embodiment relates to a composition for use as a controlled releasesystem, wherein the active pharmaceutical ingredient is selected from aprotein, which is a human growth hormone, fibroblast growth factor(FGF), erythropoietin (EPO), platelet derived growth factor (PDGF),granulocyte colony stimulating factor (g-CSF), bovine somatotropin(BST), tumor necrosis factor (TNF), transforming growth factor-beta(TGF-Beta), a cytokine, an interleukin, insulin, or interferon. Oneembodiment relates to a composition for use as a controlled releasesystem, wherein the active pharmaceutical ingredient is selected fromnucleic acids, nucleotides, nucleosides, oligonucleotides, DNA, RNA orfragments thereof. One embodiment relates to a composition for use as acontrolled release system, wherein the active pharmaceutical ingredientis a small inorganic or organic drug molecule. One embodiment relates toa composition for use as a controlled release system, wherein the activepharmaceutical ingredient is a chemotherapeutic drug for treatment ofcancer. One embodiment relates to a composition for use as a controlledrelease system, wherein the active pharmaceutical ingredients is achemotherapeutic drug selected from the class of compounds that areanti-metabolites, anti-microtubule agents, topoisomerase inhibitors,cytotoxic antibiotics, alkylating agents, checkpoint inhibitors, or aradiosensitizer, or a photosensitizer. One embodiment relates to acomposition for use as a controlled release system, wherein the activepharmaceutical ingredient is a drug that modulates an immune response.One embodiment relates to a composition for use as a controlled releasesystem, wherein the active pharmaceutical ingredient enhances the effectof radiotherapy, photodynamic therapy (PDT), hyperthermia basedtreatments such as high-intensity focused ultrasound (HIFU),radiofrequency thermal ablation (RFA), laser-therapy, or laser-inducedinterstitial thermotherapy (LITT). One embodiment relates to acomposition for use as a controlled release system, wherein the activepharmaceutical ingredient is an anesthetic.

One embodiment relates to a composition for use as a controlled releasesystem, wherein the active pharmaceutical ingredient is formulated in ananoparticle or microsphere that is dispersed in the composition. Oneembodiment relates to a composition for use as a controlled releasesystem, wherein the composition comprises contrast agents that makes thecomposition visible by PET imaging, SPECT imaging, Ultrasound imaging,CT imaging, x-ray imaging, fluoroscopy imaging, fluorescence imaging, orOCT imaging. One embodiment relates to a composition for use as acontrolled release system, wherein the composition comprises organicradioisotopes or inorganic radionuclides for use as internalradiotherapy such as brachytherapy or in imaging of tissue in humans oranimals. One embodiment relates to a composition for use as a controlledrelease system, which is administered to the human or animal bodythrough a syringe, an endoscope or a bronchoscope to the target tissuepreferably wherein the composition after insertion into the human oranimal body constitutes a medical or surgical implant for tissue orsurgical adhesion which preferably is wound dressing, a hemostat,enhances tissue regeneration, is a void filler.

Another aspect of the present relation relates to a medical or surgicalimplant comprising a composition according to any of the precedingclaims, wherein the composition is part of a sprayable composition.

In one embodiment the present invention relates to a compositioncomprising:

a. non-water soluble carbohydrates

b. a contrast agent for imaging, wherein at least 60% of the contrastagent remains within 10 cm from the injection site after 24 h for use inlocal co-administration into a human or animal body, and wherein thecomposition is a liquid before administration into the human or animalbody and increases in viscosity by more than 1,000 centipoise (cP) afteradministration.

One embodiment relates to a composition for use in localco-administration into a human or animal body according to the presentinvention, wherein the composition is a liquid before administrationinto the human or animal body that increases in viscosity by more than10,000 centipoise (cP) after administration.

In another embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body wherein thecomposition comprises an active pharmaceutical ingredient.

In another embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body wherein thecomposition comprises an active pharmaceutical ingredient, wherein theactive pharmaceutical ingredient is an anti-cancer chemotherapeuticsselected from the class of compounds that are anti-metabolites,anti-microtubule agents, topoisomerase inhibitors, cytotoxicantibiotics, alkylating agents, radiosensitizers, or arephotosensitizers.

In another embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body wherein thecomposition is an x-ray contrast agent for imaging.

In another embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body, wherein thecomposition is an X-ray contrast agent which is an organic substance.

In another embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body wherein thecomposition is an X-ray contrast agent, which comprises one or moreiodinated polymers, iodinated oligomers, iodinated lipids, iodinatedsaccharides, iodinated disaccharides, iodinated polysaccharides,iodinated peptides, or a derivative or a combination thereof.

In another embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body wherein thecomposition comprise an active pharmaceutical ingredient, wherein theactive pharmaceutical ingredient is one or more compounds selected fromthe group of anti-cancer and radiosensitizer drugs, such as irinotecanhydrochloride, nogitecan hydrochloride, exatecan, lurtotecan, docetaxelhydrate, cyclophosphamide, lifosfamide, nimustine, carboquone,chlorambucil, dacarbazine, enocitabine, gemcitabine, carmofur,cytarabine, cytarabine ocphosphate, tegafur, doxifluridine,hydroxycarbamide, 5-fluorouracil, methotrexate, mercaptopurine,fludarabine phosphate, actinomycin D, aclarubicin hydrochloride,idarubicin hydrochloride, epirubicin hydrochloride, daunorubicinhydrochloride, pirarubicin hydrochloride, bleomycin hydrochloride,zinostatin stimalamer, neocarzinostatin, mytomycin C, bleomycin sulfate,peplomycin sulfate, vinorelbine tartrate, vincristine sulfate, vindesinesulfate, vinblastine sulfate, amrubicin hydrochloride, gefitinib,exemestan, capecitabine, doxorubicin, mitomycin, paclitaxel, nitrogenmustards, etoposide, camptothecin, nicotinamide, metronidazole,oxaliplatin, cisplatin, carboplatin, camptothecin, Tirapazamine,Vinblastine, Vinorelbine, Vincristine, Daunorubicin Tamoxifen, Imatinib,Dasatinib, nilotinib, Gefrtinib, ertoinib, Sorafenib, Sunitinib,Lapatinib, Bortezomib, interferon-alfa, lnterteukin-2, Thalidomide,Lenaiidomide, Temsiroiimus, Everolimus, and the like, but not limited tothose. Active pharmaceuticals may be formulated in various forms and thepresent invention is to be seen as incorporating various forms offormulations of the active ingredient. In another embodiment the presentinvention relates to a composition for use in local co-administrationinto a human or animal body wherein the composition is a liquid beforeadministration and has the ability to transform into a gel-like materialafter administration. In another embodiment the present inventionrelates to a composition for use in local co-administration into a humanor animal body wherein the composition becomes a solid after injectionsuch as a crystalline or amorphous solid. In another embodiment thepresent invention relates to a composition for use in localco-administration into a human or animal body wherein an increase inviscosity after administration into the human or animal body is due todiffusion of a molecule out of the gel-like material and intosurrounding tissue. In another embodiment the present invention relatesto a composition for use in local co-administration into a human oranimal body wherein an increase in viscosity after administration intothe human or animal body is due to diffusion of solvent-like molecules.

In another embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body wherein atleast 50% of the non-water soluble carbohydrates are pyranose basedcarbohydrates selected from derivatives of lactose, maltose, trehalose,raffinose, glucosamine, galactosamine and lactoseamine, or mixturesthereof. In another embodiment the present invention relates to acomposition for use in local co-administration into a human or animalbody wherein at least 50% of the non-water soluble carbohydrates aredisaccharides with at least two pyranose saccharide units, or mixturesthereof. In another embodiment the present invention relates to acomposition for use in local co-administration into a human or animalbody, wherein the non-water soluble carbohydrates are disaccharides withstructures selected from:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ in formulae I, II or III areselected collectively from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; orwherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selectedfrom the group consisting of hydrogen, alkanoyl, hydroxyl-substitutedalkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstitutedalkanyl and acyloxy substituted alkanyl;

or wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selectedcollectively from the group consisting of acetyl, isobutyryl orpropionyl; or

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selectedfrom the group consisting acetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of thepreceding mentioned structural variations are claimed.

In another embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body wherein atleast 50% of the non-water soluble carbohydrates are trisaccharides or amixture of trisaccharides. In another embodiment the present inventionrelates to a composition for use in local co-administration into a humanor animal body wherein the non-water soluble carbohydrates aretrisaccharides with structures selected from:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ in formulae IVare selected collectively from the group consisting of hydrogen,alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substitutedalkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substitutedalkanyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ areindependently selected from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl;

or wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁are selected collectively from the group consisting of acetyl,isobutyryl or propionyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉,R₁₀ and R₁₁ are independently selected from the group consisting acetyl,isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of thepreceding mentioned structural variations are claimed.

In another embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body wherein atleast 50% of the non-water soluble carbohydrates are oligosaccharides ora mixture of oligosaccharides with at least 4 monosaccharide unitslinked together

In another embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body wherein atleast 50% of the non-water soluble carbohydrates are mono- oroligosaccharides containing at least one amino sugar unit. In anotherembodiment the present invention relates to a composition for use inlocal co-administration into a human or animal body wherein the at leastone amino sugar is selected from compounds with the structure:

wherein R₁, R₂, R₃, R₄ and R₅ in formulae V are selected collectivelyfrom the group consisting of hydrogen, alkanoyl, hydroxyl-substitutedalkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstitutedalkanyl and acyloxy substituted alkanyl; or wherein R₁, R₂, R₃, R₄ andR₅ are independently selected from the group consisting of hydrogen,alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substitutedalkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substitutedalkanyl, mono- di-, tri- or tetra-saccharide derivatives;

or wherein all groups of R₁, R₂, R₃, R₄ and R₅ are selected collectivelyfrom the group consisting of acetyl, isobutyryl or propionyl; or whereinR₁, R₂, R₃, R₄ and R₅ are independently selected from the groupconsisting acetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of thepreceding mentioned structural variations are claimed.

In another embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body whereinrelease of said one or more active pharmaceutical ingredients iscontrolled by mixing carbohydrates with different hydrophobicity byalteration of the substitutions on the carbohydrate hydroxyl groups. Inanother embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body wherein theactive pharmaceutical ingredient is formulated in a nanoparticle ormicrosphere that is dispersed in the composition to control the releaserate of the active pharmaceutical ingredient. In another embodiment thepresent invention relates to a composition for use in localco-administration into a human or animal body wherein the X-ray contrastagent is an inorganic acid or salt. In another embodiment the presentinvention relates to a composition for use in local co-administrationinto a human or animal body wherein the composition also comprisesparticles in the size range from 1-1000 nm, such as nanoparticles in thesize range from 2 to 500 nm. In another embodiment the present inventionrelates to a composition for use in local co-administration into a humanor animal body wherein the nanoparticles comprises gold (Au). In anotherembodiment the present invention relates to a composition for use inlocal co-administration into a human or animal body wherein thecomposition also comprises, radioactive compounds, paramagneticcompounds, fluorescent compounds or ferromagnetic compounds, or anymixture thereof. In another embodiment the present invention relates toa composition for use in local co-administration into a human or animalbody wherein the composition contains an MRI, SPECT or PET contrastagent.

In one embodiment the present invention relates to a composition for usein local co-administration into a human or animal body wherein thecomposition also comprises a molecule that increase gel stability in thehuman or animal body, selected from the group interfacially activemolecule, amphiphilic molecule, and/or emulsifier. In another embodimentthe present invention relates to a composition for use in localco-administration into a human or animal body wherein the compositionalso comprises a molecule that increase gel stability in the human oranimal body wherein said molecule that increase gel stability isselected from the group poly(ethylene glycol-b-caprolactone) (PEG-PCL),poly(D,L-lactic acid) (PLA), or poly(lactic-co-glycolic acid) (PGLA), orany combination thereof.

In one embodiment the present invention relates to a composition for usein local co-administration into a human or animal body wherein thecomposition comprises iodinated derivate of carbohydrate or iodinatedderivative of poly-alcohols, such as iodinated derivatives of sucroseacetate isobutyrate (SAIB), such as iodinated derivatives of lactose,such as iodinated derivatives of trehalose, such as iodinatedderivatives of arabinose, such as iodinated derivatives of maltose, suchas iodinated derivatives of glucose, such as iodinated derivatives ofgalactose, iodinated derivatives of glucosamine, such as iodinatedglucosamine, and the like.

In another embodiment the present invention relates to a composition foruse in local co-administration into a human or animal body wherein thecomposition comprises an iodinated derivate of a carbohydrate doped intoa composition of the same class of non-idoninated carbohydratederivatives. In another embodiment the present invention relates to acomposition for use in local co-administration into a human or animalbody in combination with radio-therapy. In another embodiment thepresent invention relates to a composition for use in localco-administration into a human or animal body for use as a tissuemarker.

Another aspect of the present invention relates to a method of recordingan X-ray image of the body of a mammal, comprising the steps of

a. providing an X-ray contrast composition comprising an organic X-rayagent in a non-water soluble carbohydrate gel-forming system;

b. administering the X-ray contrast composition to a predeterminedlocation of the mammal, and

c. recording X-ray-based images of at least a part of the body whichcomprises the predetermined location.

Yet another aspect of the present invention relates to a method of jointradiotherapy and X-ray imaging of a target tissue in a mammal,comprising the steps of

a. providing an X-ray contrast composition comprising an organic X-rayagent in a non-water soluble carbohydrate gel-forming system;

b. administering the X-ray contrast composition to a predeterminedtarget tissue of the mammal,

c. recording X-ray-based images, of at least a part of the body whichcomprises the target tissue, thereby providing a definition of thetarget tissue, and

d. using the definition of the target tissue obtained in c) to directexternal beam radiotherapy to the target tissue.

Yet another aspect of the present invention relates to a method fordirecting local administration of a pharmaceutically active agent to atarget tissue in a mammal, comprising the steps of

a. providing an X-ray contrast composition comprising an organic X-rayagent in a non-water soluble carbohydrate gel-forming system;

b. administering the X-ray contrast composition to a predeterminedtarget tissue of the mammal,

c. recording X-ray-based images, of at least a part of the body whichcomprises the target tissue, thereby providing a definition of thetarget tissue, and

d. using the X-ray contrast composition in b) to further comprise anactive pharmaceutical agent for delivery of an active pharmaceuticalagent to a predetermined target tissue of the mammal.

In another embodiment the present invention relates to a method for acomposition for use in local co-administration into a human or animalbody wherein at least 50% of the non-water soluble carbohydrates arepyranose based carbohydrates selected from derivatives of lactose,maltose, trehalose, raffinose, glucosamine, galactosamine andlactoseamine, or mixtures thereof. In another embodiment the presentinvention relates to a method for a composition for use in localco-administration into a human or animal body wherein the non-watersoluble carbohydrates are disaccharides with at least two pyranosesaccharide units. In another embodiment the present invention relates toa method for a composition for use in local co-administration into ahuman or animal body wherein the non-water soluble carbohydrates aredisaccharides with structures selected from:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ in formulae I, II or III areselected collectively from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; orwherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selectedfrom the group consisting of hydrogen, alkanoyl, hydroxyl-substitutedalkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstitutedalkanyl and acyloxy substituted alkanyl;

or wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selectedcollectively from the group consisting of acetyl, isobutyryl orpropionyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ areindependently selected from the group consisting acetyl, isobutyryl orpropionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of thepreceding mentioned structural variations are claimed.

In another embodiment the present invention relates to a method for acomposition for use in local co-administration into a human or animalbody wherein the non water soluble carbohydrates are trisaccharides or amixture of trisaccharides. In another embodiment the present inventionrelates to a method for a composition for use in local co-administrationinto a human or animal body wherein the non-water soluble carbohydratesare trisaccharides with structures selected from:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ in formulae IVare selected collectively from the group consisting of hydrogen,alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substitutedalkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substitutedalkanyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ areindependently selected from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl;

or wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁are selected collectively from the group consisting of acetyl,isobutyryl or propionyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉,R₁₀ and R₁₁ are independently selected from the group consisting acetyl,isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of thepreceding mentioned structural variations are claimed. In anotherembodiment the present invention relates to a method for a compositionfor use in local co-administration into a human or animal body whereinthe non water soluble carbohydrates are oligosaccharides with at least 4monosaccharide units linked together. In another embodiment the presentinvention relates to a method for a composition for use in localco-administration into a human or animal body wherein the non watersoluble carbohydrates are mono- or oligosaccharides containing at leastone amino sugar unit.

In another embodiment the present invention relates to a method for acomposition for use in local co-administration into a human or animalbody wherein the amino sugars are selected from compounds with thestructure:

wherein R₁, R₂, R₃, R₄ and R₅ in formulae V are selected collectivelyfrom the group consisting of hydrogen, alkanoyl, hydroxyl-substitutedalkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstitutedalkanyl and acyloxy substituted alkanyl; or wherein R₁, R₂, R₃, R₄ andR₅ are independently selected from the group consisting of hydrogen,alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substitutedalkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substitutedalkanyl, carbohydrates and carbohydrate derivatives;

or wherein all groups of R₁, R₂, R₃, R₄ and R₅ are selected collectivelyfrom the group consisting of acetyl, isobutyryl or propionyl; or whereinR₁, R₂, R₃, R₄ and R₅ are independently selected from the groupconsisting acetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of thepreceding mentioned structural variations are claimed.

In another embodiment the present invention relates to a method for acomposition for use in local co-administration into a human or animalbody wherein the target tissue comprises undesirably growing cells.

In another embodiment the present invention relates to a method for acomposition for use in local co-administration into a human or animalbody wherein the target tissue comprises tumor cells. In anotherembodiment the present invention relates to a method for a compositionfor use in local co-administration into a human or animal body whereinsteps (c) and (d) are performed simultaneously.

In another aspect, the present invention relates to a method for acomposition for use in local co-administration into a human or animalbody, which is administered to the human or animal body through asyringe, an endoscope or a bronchoscope to the target tissue preferablywherein the composition after insertion into the human or animal bodyconstitutes a medical or surgical implant for tissue or surgicaladhesion.

In yet another aspect, the present invention relates to a medical orsurgical implant for use in local co-administration into a human oranimal body wherein, wherein the composition is part of a sprayablecomposition.

In yet another aspect, the present invention relates a method for localadministration of a composition for use in local co-administration,wherein an active pharmaceutical ingredient is released specificallyinto tissue in need thereof, preferably tumor tissue. In one embodiment,the present invention relates to a method for a composition for use inlocal co-administration with or without an active pharmaceuticalingredient into a human or animal body wherein the tissue is comprisingan interorgan space such as an intraperitoneal space, a muscle, adermis, an epidermis, a natural lumen or void, an abdominal cavity, aprostate, a rectum, a location between two or more organs such as aprostate and a rectum, a heart and lung, a lymph node and anothertissue, a breast, a tissue between a radiation target and healthytissue, and a vasculature.

In one embodiment the present invention relates to a composition for usein controlled release of at least one active pharmaceutical ingredientthat modulates an immunogenic response in a human or animal body, saidcomposition comprising non-water soluble carbohydrates and wherein thecomposition is a liquid before administration into the human or animalbody and increases in viscosity by more than 1,000 centipoise (cP) afteradministration. In one embodiment the present invention relates to acomposition for use in controlled release of at least one activepharmaceutical ingredient, wherein the composition is a liquid beforeadministration into the human or animal body that increases in viscosityby more than 10,000 centipoise (cP) after administration into the humanor animal body. In one embodiment the present invention relates to acomposition for use in controlled release of at least one activepharmaceutical ingredient, wherein the composition is a liquid beforeadministration and becomes a gel-like material or solid material, suchas an crystalline solid or an amorphous solid, after administration. Inone embodiment the present invention relates to a composition for use incontrolled release of at least one active pharmaceutical ingredient,wherein an increase in viscosity after administration into the human oranimal body is due to diffusion of a molecule out of the administeredmaterial and into surrounding tissue. In one embodiment the presentinvention relates to a composition for use in controlled release of atleast one active pharmaceutical ingredient, wherein an increase inviscosity after administration into the human or animal body is due todiffusion of solvent-like molecules. In one embodiment the presentinvention relates to a composition for use in controlled release of atleast one active pharmaceutical ingredient In one embodiment the presentinvention relates to a composition for use in controlled release of atleast one active pharmaceutical ingredient, wherein at least 50% of thenon-water soluble carbohydrates are selected from derivatives ofglucose, galactose, mannose, lactose, maltose, trehalose, raffinose,glucosamine, galactosamine, and lactoseamine. In one embodiment thepresent invention relates to a composition for use in controlled releaseof at least one active pharmaceutical ingredient In one embodiment thepresent invention relates to a composition for use in controlled releaseof at least one active pharmaceutical ingredient, wherein said at leastone active pharmaceutical ingredient is an immune-modulating compoundwhich is a ligand for intracellular proteins and/or receptors; or aligand for cell surface proteins and/or receptors. In one embodiment thepresent invention relates to a composition for use in controlled releaseof at least one active pharmaceutical ingredient, wherein saidintracellular proteins and/or receptors are selected from the groupconsisting of NOD-like receptor (NLR) family and the subfamilies NLRA,NLRB, NLRC, NLRP, NODs, NALP, IPAF, HLA complexes, RIG-I-like receptors,cytokine receptors, interleukin receptors, CD proteins, CTLA proteins,PD1, T Cell receptor, B cell receptor, and theToll-like-receptor (TLR)family; TLR1, TLR2 TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10,TLR11, TLR12, TLR13. In one embodiment the present invention relates toa composition for use in controlled release of at least one activepharmaceutical ingredient, wherein the active pharmaceutical ingredientelicit immunogenicity that is a humoral and/or cell-mediated immuneresponse. In one embodiment the present invention relates to acomposition for use in controlled release of at least one activepharmaceutical ingredient, wherein said at least one activepharmaceutical ingredient is an immuno stimulating compound selectedfrom the group consisting of polyinosinic:polycytidylic acid (poly I:C),Polyadenylic-polyuridylic acid (poly A:U), poly I:C-poly-L-lysine(poly-ICLC), poly-ICR, CL264,N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-(R)-cysteine-(S)serine-(S)lysine 4 (Pam₃Cys), Monophosphoryl lipid A(MPLA) and other lipopolysaccharides, alpha-galactosylceramide,Propirimine, Imiquimod (R837), resiquimod (R848), TMX-101, TMX- 201,TMX-202, Gardiquimod, R850 (3M Pharma), R851 (3M Pharma), 852A (3MPharma), S-27610, 3M-002 (CL075), 3M-003, 3M-005, 3M-006, 3M-007,3M-012, 3M-13, 3M-031,3M-854 (3M Pharma), CL097, CL264, IC-31,Loxoribine and other imidazoquinolines, ssPolyU, sotirimod (3M Pharma),Isatoribine (Anadys), ANA975 (Anadys/Novartis), SM360320 (Sumitomo),R1354 (Coley Pharmaceuticals) single stranded or double stranded RNA,ORN 02 (5′-UUAUUAUUAUUAUUAUUAUU-3′), ORN 06 5′-UUGUUGUUGUUGUUGUUGUU-3′,CpG-ODN DSLIM (Mologen), AVE 0675 (Coley Pharmaceuticals), CpG Boligodeoxynucleotide (ODN) 1018 (Dynavax Technologies), AZD 1419(Dynavax), ODN 1982, CpG B ODN 2006 (Coley Pharmaceuticals), IMO 2125(Idera Pharma), CpG A ODN 2216, CpG A ODN 2336, CpG 2395, CpG ODN 7909(Coley Pharmaceuticals), CpG 10101 (Coley Pharmaceuticals), CpG ODNAVE0675 (Coley Pharmaceuticals), CpG ODN HYB2093 (IderaPharmaceuticals/Novartis), CpG ODN HYB2055 (Idera Pharmaceuticals),CpG-ODN IMO-2125 (Idera Pharmaceuticals), CpG C ODN M362, Tolamba (Amba1 ragweed allergen with covalently linked CpG B class ODN 1018)(DynavaxTechnologies), Heplisav (Dynavax Technologies), 10181SS (DynavaxTechnologies), IM02055 (Idera Pharmaceuticals), IRS954 (DynavaxTechnologies), (flagellin, muramyl dipeptide, saponins such as QS21,Leishmania elongation factor, SB-AS4, threonyl-muramyl dipeptide,L18-MDP, mifamurtid, and OM-174. In one embodiment the present inventionrelates to a composition for use in controlled release of at least oneactive pharmaceutical ingredient In one embodiment the present inventionrelates to a composition for use in controlled release of at least oneactive pharmaceutical ingredient, wherein said at least one activepharmaceutical ingredient is an immuno suppressive compound comprising asteroid selected from the group consisting of 21-Acetoxyprefnenolone,Aalclometasone, Algestone, Amicinonide, Beclomethasone, Betamethasone,Betamethasone dipropionate, Betamethasone hemisuccinate, Budesonide,Chloroprednisone, Clobetasol, Blovetasone, Clocortolone, Cloprednol,Corticosterone, Cortisone, Cortivazol, Deflazacort, Desonide,Desoximethasone, dexamethason, Dexamethasone palmitate, Dexamethasonephosphate, Diflorasone, Diflucortolone, Difluprednate, Enoxolone,Fluazacort, Flucloronide, Flumethasone, Flunisolide, FluocinoloneAcetonide, Fludrocortisone, Fluocinonide, Fluocortin Butyl,Fluocortolone, Fluorometholone, Fluperolone, Fluprednidine,Fluprednisolone, Flurandrenolide, Formocortal, Halcinonide,Glucocorticoids, Halomethasone, Halopredone, Hydrocortamate,Hydrocortisone, Limethasone, Mazipredone, Medrysone, Meprednisone,Methyolprednisolone, Methyolprednisolone hemisuccinate, MometasoneFuroate, Paramethasone, Prednicarbate, Prednisolone, Prednisolonepalmitate, Prednisolone phosphate, Prednisone, Prednival, Prednylidene,Tixocortal, and Triamcinolone. In one embodiment the present inventionrelates to a composition for use in controlled release of at least oneactive pharmaceutical ingredient, wherein said at least one activepharmaceutical ingredient is an immune-suppressive compound comprising asmall molecule inhibitor acting on cellular targets selected from thegroup consisting of c-Fms, PDGFR␣, Abl, PDGFR␣, NFkB, IkB, JAK1, JAK2,JAK3, GSK3, p38 MAPK, JNK, KIT, EGFR, ERBB2, ERBB4, VEGFR1, VEGFR2,VEGFR3, FLT3, PKC□, RAF1, CDK1, CDK2, CDK4, NLRP3, IRF3, STAT1, STAT2,STAT3, STAT4, STATS, STATE, JAK, Hsp90, Hsp70, PI3K, mTOR, AKT, DNA-PK,ATM, AMPK, PDK-1, S6 kinase, RIP2, TRIF, MYD88, TAK1, PTK2 (FAK), TAK1,Ras, Raf, Mek, Erk, GLUT1, GLUT2, HK1, HK2, Ca9, HIF-1, HIF-2, HIF-3,PHD1, PHD2, PHD3, ALK.

In one embodiment the present invention relates to a composition for usein controlled release of at least one active pharmaceutical ingredient,wherein said at least one active pharmaceutical ingredient is an immunosuppressive compound comprising a small molecule inhibitor acting onintracellular targets selected from the group consisting ofindomethacin, CLI-095 (C15H17CIFNO4S, CAS#243984-11-4), Bay11-7082(C10H9NO2S, CAS#19542-67-7), Triptolide (PG 490), CGP53716, SU9518,PD166326, Celastrol, Tripterin, BIRB-796 (Doramapimod), SB 203580,SB202190, VX-702, NVP-BEZ235, GDC-0980 (RG7422), Ridaforolimus(Deforolimus, AP23573), Nilotinib (Tasigna, AMN107), Sorafenib tosylate(Nexavar), Dasatinib (Sprycel, BMS-354825), MLN518 (CT53518), Vatalanib(PTK787/ZK222584), OSI-930, AZD2171, Pazopanib (Votrient), IPI-504(retaspimycin), Deforolimus (Ridaforolimus), GDC-0980 (RG7422,C₂₃H₃₀N₈O₃S, CAS#1032754-93-0), Palomid 529 (C₂₄H₂₂O₆ CAS#914913-88-5),Imatinib mesylate (Gleevec/Glivec), Everolimus (Afinitor, RAD001),Sirolimus (Rapamune, rapamycin), Temsirolimus (Torisel, CCI-779),Bortezomib (Velcade), Gefitinib (Iressa), Canertinib (CI-1033, CAS#267243-28-7, C₂₄H₂₅ClFN₅O₃), Erlotinib hydrochloride (Tarceva),Pelitinib (EKB-569) (C₂₄H₂₃ClFN₅O₂, CAS#257933-82-7), Vandetanib(Zactima, ZD6474, C₂₂H₂₄BrFN₄O₂, CAS No.: 443913-73-3), Sunitinib(Sutent, SU-11248, C₂₂H₂₇FN₄O₂.C₄H₆O₅, CAS No.: 341031-54-7), Tandutinib(MLN518), C₃₁H₄₂N₆O₄, CAS No.: 387867-13-2, Roscovitine (Seliciclib),C₁₉H₂₆N₆O, CAS No.: 186692-46-6. In one embodiment the present inventionrelates to a composition for use in controlled release of at least oneactive pharmaceutical ingredient, wherein said at least one activepharmaceutical ingredient is an anti-infectious compound selected fromthe group consisting of Rifampicin, dideoxycytidine-5″-triphosphate,Clarithromycin, acyclovir, ciprofloxacin, fusidin, gentamicin,chloramphenicol, levofloxacin, oxytetracyclin, tobramycin,natriumcromoglicat, Amoxicillin, Ampicillin., Pivampicillin, Ertapenem,Meropenem, Doripenem, Cefotaxim, Ceftazidim, Ciprofloxacin,Valaciclovir, efavirenz, emtricitabin, tenofovirdisoproxil, Rilpivirine,penicillin, Trimethoprim-sulfamethoxazole, rifampicin, etambutol,isoniazid, pyrazinamide, voriconazole, amphotericin B, caspofungin,flucytosine, itraconazole, doxycyclin, sulfonamides, andsulfamethoxazole. In one embodiment the present invention relates to acomposition for use in controlled release of at least one activepharmaceutical ingredient, wherein said at least one activepharmaceutical ingredient is an immunomodulating compound selected fromthe group consisting of thalidomide, lenalidomide and pomalidomide,sargramostim, IL-2, interferon-alfa, alemtuzumab, bevacizumab,brentuximab vedotin, cetuximab, gemtuzumab, ozogamicin, ibritumomab,tiuxetan, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab,trastuzumab, loxoribine, bropirimine, pomalidomide, sargramostim. In oneembodiment the present invention relates to a composition for use incontrolled release of at least one active pharmaceutical ingredient,further comprising at least one antigen. In one embodiment the presentinvention relates to a composition for use in controlled release of atleast one active pharmaceutical ingredient, wherein at least 50% of thenon-water soluble carbohydrates are disaccharides with at least twopyranose saccharide units, or mixtures thereof. In one embodiment thepresent invention relates to a composition for use in controlled releaseof at least one active pharmaceutical ingredient, wherein the non-watersoluble carbohydrates are disaccharides with structures selected from:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ in formulae I, II and III areselected collectively from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; orwherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selectedfrom the group consisting of hydrogen, alkanoyl, hydroxyl-substitutedalkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstitutedalkanyl and acyloxy substituted alkanyl;

or wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selectedcollectively from the group consisting of acetyl, isobutyryl orpropionyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ areindependently selected from the group consisting acetyl, isobutyryl orpropionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

In one embodiment the present invention relates to a composition for usein controlled release of at least one active pharmaceutical ingredient,wherein at least 50% of the non-water soluble carbohydrates aretrisaccharides, or mixtures thereof. In one embodiment the presentinvention relates to a composition for use in controlled release of atleast one active pharmaceutical ingredient, wherein the non-watersoluble carbohydrates are trisaccharides with structures selected from:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ in formulae IVare selected collectively from the group consisting of hydrogen,alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substitutedalkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substitutedalkanyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ areindependently selected from the group consisting of hydrogen, alkanoyl,hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl,alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl;

wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁are selected collectively from the group consisting of acetyl,isobutyryl or propionyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉,R₁₀ and R₁₁ are independently selected from the group consisting acetyl,isobutyryl or propionyl;

and wherein both pure anomers and mixtures of α- and β-anomers of theabove mentioned structural variations are claimed.

In one embodiment the present invention relates to a composition for usein controlled release of at least one active pharmaceutical ingredient,wherein at least 50% of the non-water soluble carbohydrates areoligosaccharides or a mixture of oligosaccharides with at least 4monosaccharide units linked together. In one embodiment the presentinvention relates to a composition for use in controlled release of atleast one active pharmaceutical ingredient, wherein at least 50% of thenon-water soluble carbohydrates are mono- or oligosaccharides containingat least one amino sugar unit. In one embodiment the present inventionrelates to a composition for use in controlled release of at least oneactive pharmaceutical ingredient, wherein the non-water solublecarbohydrates are amino sugars selected from compounds with thestructure:

wherein R₁, R₂, R₃, R₄ and R₅ in formulae V are selected collectivelyfrom the group consisting of hydrogen, alkanoyl, hydroxyl-substitutedalkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstitutedalkanyl and acyloxy substituted alkanyl; or wherein R₁, R₂, R₃, R₄ andR₅ are independently selected from the group consisting of hydrogen,alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substitutedalkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substitutedalkanyl, mono- di-, tri- or tetra-saccharide derivatives;

wherein all groups of R₁, R₂, R₃, R₄ and R₅ are selected collectivelyfrom the group consisting of acetyl, isobutyryl or propionyl; or whereinR₁, R₂, R₃, R₄ and R₅ are independently selected from the groupconsisting acetyl, isobutyryl or propionyl;

and wherein both pure anomers and mixtures of anomers such as α- andβ-anomer centres of the above mentioned structural variations areclaimed.

In one embodiment the present invention relates to a composition for usein controlled release of at least one active pharmaceutical ingredient,wherein the release of one or more active pharmaceutical ingredients iscontrolled by mixing carbohydrates with different hydrophobicity byalteration of the substitutions on the carbohydrate hydroxyl groups. Inone embodiment the present invention relates to a composition for use incontrolled release of at least one active pharmaceutical ingredient,wherein the composition also comprises a molecule that increase gelstability in the human or animal body, such as an interfacially activemolecule, such as an amphiphilic molecule, such as an emulsifier. In oneembodiment the present invention relates to a composition for use incontrolled release of at least one active pharmaceutical ingredient,wherein the composition comprises contrast agents that makes thecomposition visible by PET imaging, SPECT imaging, Ultrasound imaging,CT imaging, x-ray imaging, fluoroscopy imaging, fluorescence imaging, orOCT imaging. In one embodiment the present invention relates to acomposition for use in controlled release of at least one activepharmaceutical ingredient, wherein the active pharmaceutical ingredientis formulated in a nanoparticle or microsphere that is dispersed in thecomposition. In one embodiment the present invention relates to acomposition for use in controlled release of at least one activepharmaceutical ingredient, in combination with radiotherapy,photodynamic therapy (PDT), hyperthermia based treatments such ashigh-intensity focused ultrasound (HIFU), radiofrequency thermalablation (RFA), laser-therapy, or laser-induced interstitialthermotherapy (LITT). In one embodiment the present invention relates toa composition for use in controlled release of at least one activepharmaceutical ingredient, which is administered to the human or animalbody through a syringe, an endoscope or a bronchoscope to the targettissue preferably wherein the composition after insertion into the humanor animal body constitutes a medical or surgical implant for tissue orsurgical adhesion which preferably is wound dressing, a hemostat,enhances tissue regeneration, or is a void filler. In one embodiment thepresent invention relates to a composition for use in controlled releaseof at least one active pharmaceutical ingredient, wherein thecomposition comprises organic radioisotopes or inorganic radionuclidesfor use as internal radiotherapy such as brachytherapy or in imaging oftissue in humans or animals.

Another aspect of the present invention relates to a medical or surgicalimplant comprising the composition according to any of the precedingclaims, wherein the composition is part of a sprayable composition.

Another aspect of the present invention relates to use of a compositionaccording to the present invention, for injecting into tumor tissue. Inone embodiment the present invention relates to use of a composition foruse in controlled release of at least one active pharmaceuticalingredient, in combination with external beam radiotherapy.

Yet another aspect of the present invention relates to a method forlocal administration of composition for use in controlled release of atleast one active pharmaceutical ingredient, wherein the activepharmaceutical ingredient is released specifically into tissue in needthereof, preferably tumor tissue.

In one embodiment the present invention relates to a composition for usein controlled release of at least one active pharmaceutical ingredientin tissue, said tissue comprising an intraperitoneal space, a muscle, adermis, an epidermis, a natural lumen or void, an abdominal cavity, aprostate, a rectum, a location between a prostate and a rectum, abreast, a tissue between a radiation target and healthy tissue, and avasculature.

In one embodiment, the present invention relates to a method for acomposition for use in local co-administration with or without an activepharmaceutical ingredient into a human or animal body wherein the tissueis comprising an interorgan space such as an intraperitoneal space, amuscle, a dermis, an epidermis, a natural lumen or void, an abdominalcavity, a prostate, a rectum, a location between two or more organs suchas a prostate and a rectum, a heart and lung, a lymph node and anothertissue, a breast, a tissue between a radiation target and healthytissue, and a vasculature.

EXAMPLE I Synthesis

General experimental conditions: All reactions were carried out underinert atmosphere (N₂). Water sensitive liquids and solutions weretransferred via syringe. Water used for washing of the syntheses was inall cases pure MiliQ water. Organic solutions were concentrated byrotary evaporation at 30-60° C. under 200-0 millibar. Thin layerchromatography (TLC) was carried out using aluminium sheets pre-coatedwith silica 60F (Merck 5554). The TLC plates were inspected under UVlight or developed using a cerium ammonium sulphate solution (1%cerium(IV)sulphate and 2.5% hexa-ammonium molybdate in a 10% sulfuricacid solution).

Reagents: Chemicals were all purchased from Sigma Aldrich and were usedas received. Dry pyridine was obtained by drying over sieves (4 Å) for2-3 days prior to use.

Instrumentation: Nuclear Magnetic Resonance (NMR) was conducted on aBruker Ascend™ 400 MHz—operating at 401.3 MHz for ¹ H and 100.62 MHz for¹³C— with a 5 mm H-Broadband Dual Channel z-gradient Prodigy cryoprobe.All NMR spectra were acquired at 298 K. The FID files were processed inMnova Suite version 8.1.4. All NMR spectra were recorded in CDCl₃, thesignal at 7.26 ppm (singlet) and 77.16 ppm (triplet) were used forreferencing in ¹H-NMR and ¹³C-NMR spectra, respectively. In ¹H-NMRspectra of α,β anomeric mixtures, the integral of H-1 of the mostabundant anomer was always set to 1.0, and the percentage of eachanomeric species was calculated from the integral ratio of H-1 α and H-1β. MALDI-TOF MS was conducted on a Bruker Autoflex Speed™ instrument.The matrix used for MALDI-TOF was a mixture of 2,5 dihydroxy benzoicacid (DHB), trifluoroacetic acid and Na⁺ in ethanol.

D-Glucosamine Esters: α-D Glucosamine Pentaacetate:

D-Glucosamine HCl (2 g, 9.3 mmol) was suspended in 10 mL dry CH₂Cl₂under inert atmosphere (N₂) and cooled to 0° C. Hereafter, aceticanhydride (10 mL, 106 mmol, ˜2.3 eq pr. OH) was carefully added followedby addition of dry pyridine (10 mL) and a catalytic amount of DMAP (117mg, 0.96 mmol, ˜0.1 eq). The reaction slowly returned to r.t. and wascontinued at this temperature for 30 h, whereafter the temperature waselevated to 40° C. and continued for another 32 h. Then TLC (acetone:toluene 1:1, Rf product ˜0.6) showed that the reaction was completed.The reaction mixture was concentrated in vacuuo and co-evaporated withtoluene. The concentrate was re-dissolved in CHCl₃ (100 mL) and washedwith NaHCO₃ (aq) (4×100 mL) and water (2×100 mL). The pure α-anomer wasisolated by re-crystallization from isopropanol-hexane. Yield: 2.2 g(61%). ¹H NMR (400 MHz, CDCl₃) δ 6.15 (d, J=3.6 Hz, 1H), 5.63 (d, J=9.0Hz, 1H), 5.26-5.15 (m, 2H), 4.52-4.41 (m, 1H), 4.23 (dd, J=12.5, 4.1 Hz,1H), 4.04 (dd, J=12.5, 2.4 Hz, 1H), 3.98 (ddd, J=9.8, 4.1, 2.4 Hz, 1H),2.17 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 1.92 (s, 3H).¹³CNMR (101 MHz, CDCl₃) δ 171.8, 170.8, 170.1, 169.2, 168.7, 90.8, 70.8,69.8, 67.6, 61.6, 51.1, 51.04, 23.1, 21.0, 20.8 (2C), 20.7. MALDITOF-MS: Calc [M+Na]⁺: 412.35. Found: 412.33.

α-D Glucosamine Pentapropionate:

D-Glucosamine HCl (2 g, 9.3 mmol) was suspended in 10 mL dry CH₂Cl₂under inert atmosphere (N₂) and cooled to 0° C. Hereafter, propionicanhydride (13 mL, 101.4 mmol, ˜2.2 eq pr. OH) was carefully addedfollowed by dry pyridine (11.5 mL) and a catalytic amount of DMAP (113mg, 0.93 mmol,˜0.1 eq). The reaction slowly returned to r.t. andremained at this temp. for 2 h, whereafter the reaction was heated to40° C. and continued at this temperature for 56 h. Then TLC (acetone:toluene 1:2, Rf product ˜0.5) showed that the reaction was completed.The reaction was then concentrated in vacuuo and co-evaporated withtoluene. The concentrate was dissolved in CHCl₃ (100 mL) and washed withNaHCO₃ (aq) (3×100 mL) and water (2×100 mL). The organic phase was thendried with MgSO₄(s), filtered and concentrated under reduced pressure.The pure α-anomer was isolated by re-crystallization from isopropanol.Yield: 2.6 g (61%). ¹H NMR (400 MHz, CDCl₃) δ 6.18 (d, J=3.6 Hz, 1H, H-1α), 5.50 (d, J=8.9 Hz, 1H), 5.30-5.17 (m, 2H), 4.52-4.44 (m, 1H), 4.23(dd, J=12.5, 4.4 Hz, 1H), 4.06 (dd, J=12.5, 2.2 Hz, 1H), 3.98 (ddd,J=9.7, 4.4, 2.2 Hz, 1H), 2.44 (q, J=7.5 Hz, 2H), 2.40-2.21 (m, 6H), 2.12(2×q, J=7.5 Hz, 2H), 1.24-1.02 (m, ˜15H). ¹³C NMR (101 MHz, CDCl₃) δ175.3, 174.2, 173.7, 172.7, 172.2, 90.7, 70.7, 70.0, 67.4, 61.6, 51.2,51.08, 29.6, 27.7, 27.6, 27.5, 27.4, 9.7, 9.2 (2C), 9.1 (2C). MALDITOF-MS: Calc [M+Na]⁺: 482.49. Found: 482.50.

α,β-D Glucosamine Pentapropionate:

D-Glucosamine HCl (2 g, 9.3 mmol) was suspended in 10 mL dry CH₂Cl₂under inert atmosphere (N₂) and cooled to 0° C. Hereafter, propionicanhydride (13 mL, 101.4 mmol, ˜2.2 eq pr. OH) was carefully addedfollowed by dry pyridine (11.5 mL) and a catalytic amount of DMAP (114.5mg, 0.94 mmol, ˜0.1 eq). The reaction slowly returned to r.t. andremained at this temp. for 1 h, whereafter the reaction was heated to40° C. and continued at this temperature for 36 h. Then TLC (acetone:toluene 1:2, Rf products ˜0.45) showed that the reaction was completed.The reaction was then concentrated in vacuuo and co-evaporated withtoluene. The concentrate was dissolved in CHCl₃ (100 mL) and washed withNaHCO₃ (aq) (3×100 mL) and water (2×100 mL). The organic phase was thendried with MgSO₄(s), filtered and concentrated under reduced pressure,and an amorphous glass was obtained. Yield: 3,1 g (73%) (mixture ofanomers: ˜91% α and ˜9% β). ¹H NMR (400 MHz, Chloroform-d) δ 6.18 (d,J=3.6 Hz, 1H, H-1 α), 5.69 (d, J=8.8 Hz, 0.1 H, H-1 β), 5.51 (d, J=9.0Hz, 1H), 5.30-5.07 (m, 2H), 4.52-4.43 (m, 1H), 4.39-4.26 (m, 0.2H), 4.23(dd, J=12.4, 4.4 Hz, 1H), 4.12 (dd, J=12.6, 2.3 Hz, 0.1H), 4.06 (dd,J=12.5, 2.2 Hz, 1H), 3.98 (ddd, J=9.6, 4.3, 2.2 Hz, 1H, H-5 α), 3.79(ddd, J=9.4, 4.6, 2.1 Hz, 0.1H, H-5 β), 2.50-2.05 (m, ˜11H), 1.23-1.01(m, ˜17H).MALDI TOF-MS: Calc [M+Na]⁺: 482.49. Found: 482.50.

α-D Glucosamine Pentaisobutyrate:

D-Glucosamine HCl (2 g, 9.3 mmol) was suspended in 10 mL dry CH₂Cl₂under inert atmosphere (N₂) and cooled to 0° C. Hereafter, isobutyricanhydride (17 mL, 102.5 mmol, ˜2.2 eq pr. OH) was carefully addedfollowed by addition of dry pyridine (11.5 mL) and a catalytic amount ofDMAP (113 mg, 0.93 mmol, ˜0.1 eq). The reaction slowly returned to r.t.and remained at this temp. for 2 h, whereafter the reaction was heatedto 40° C. and continued at this temperature for 58 h. Then TLC (acetone:toluene 1:2, Rf product ˜0.6) showed that the reaction was completed.The reaction was concentrated in vacuuo and co-evaporated with toluene.Then, the concentrate was dissolved in CHCl₃ (100 mL) and washed withNaHCO₃ (aq) (3×100 mL) and water (2×100 mL). The organic phase was thendried with MgSO₄(s), filtered and concentrated under reduced pressure.The pure α-anomer was isolated by recrystallization from isopropanol.Yield: 2.95 g (60%). ¹H NMR (400 MHz, CDCl₃) δ 6.19 (d, J=3.6 Hz, 1H),5.52 (d, J=8.7 Hz, 1H), 5.34-5.13 (m, 2H), 4.55-4.35 (m, 1H), 4.15 (dd,J=12.4, 4.7 Hz, 1H), 4.09 (dd, J=12.4, 2.2 Hz, 1H), 3.99 (ddd, J=9.6,4.7, 2.2 Hz, 1H), 2.72 -2.44 (m, 4H), 2.25 (hept, J=7.2 Hz, 1H), 1.24(d, J=1.5 Hz, 3H), 1.22 (d, J=1.5 Hz, 3H), 1.18-1.03 (m, ˜24H). ¹³C NMR(101 MHz, CDCl₃) δ 178.1, 176.8, 176.6, 175.2, 174.7, 90.5, 70.4, 70.2,67.0, 61.6, 51.5, 35.6, 34.2, 34.1, 34.0 (2C), 19.5, 19.4, 19.1 (2C),19.0 (2C), 18.9 (4C). MALDI TOF-MS: Calc [M+Na]⁺: 552.62. Found: 552.64.

Trehalose Esters: Trehalose Octaacetate:

D-Trehalose dihydrate (2 g, 5.3 mmol) was suspended in 20 mL drypyridine under inert atmosphere (N₂) followed by addition of aceticanhydride (9 mL, 95.4 mmol, ˜2.3 eq pr. OH) and a catalytic amount ofDMAP (70.9 mg, 0.6 mmol , ˜0.1 eq). The reaction was conducted at r.t.overnight. After 15 h, the reaction temperature was re-adjusted to 48°C., and the reaction continued at this temperature for an additional 28h after which TLC (20% acetone, toluene, rf product ˜0.4) showed, thatthe reaction was done. Then followed concentration in-vacuuo andco-evaporation with toluene. The concentrate was re-dissolved in CHCl₃(100 mL) and washed with NaHCO₃ (aq) (3×100 mL) and water (2×100 mL).The organic phase was dried with MgSO₄ (s), filtered, concentrated underreduced pressure and dried in vacuuo. Yield: 3.1 g (86%). ¹H NMR (400MHz, CDCl₃) δ 5.49 (dd, J=10.3, 9.3 Hz, 2H), 5.28 (d, J=3.9 Hz, 2H),5.09-4.99 (m, 4H), 4.23 (dd, J=12.0, 5.5 Hz, 2H), 4.05 (ddd, J=10.3,5.5, 2.0, 2H), 4.05-3.96 (m, 2H), 2.08 (s, 6H), 2.07 (s, 6H), 2.05 (s,6H), 2.03 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 170.7 (2C), 170.1 (2C),169.7 (4C), 92.4 (2C), 70.1 (2C), 70.0 (2C), 68.6 (2C), 68.3 (2C), 61.9(2C), 20.8 (2C), 20.7 (6C).MALDI-TOF-MS: Calc. [M+Na]⁺: 701.59. Found:701.55.

Trehalose Octapropionate:

D-Trehalose dihydrate (2 g, 5.3 mmol) was suspended in 20 mL drypyridine under inert atmosphere (N₂) followed by addition of propionicanhydride (12 mL, 93.6 mmol, ˜2.2 eq pr. OH) and a catalytic amount ofDMAP (73.1 mg, 0.6 mmol , ˜0.1 eq). The reaction was conducted at 48° C.for 39 h, whereafter TLC (10% acetone, toluene, Rf product ˜0.4) showedthat the reaction was completed. Then followed concentration in vacuuoand co-evaporation with toluene. The crude concentrate was dissolved inCHCl₃ (100 mL) and and washed with NaHCO₃ (aq) (3×100 mL) and water(2×100 mL). The organic phase was dried with MgSO₄ (s), filtered,concentrated under reduced pressure and dried in vacuuo. Yield: 3.5 g(84.2%). ¹H NMR (400 MHz, CDCl₃) δ 5.51 (dd, J=10.2, 9.3 Hz, 2H), 5.30(d, J=3.8 Hz, 2H), 5.11-5.02 (m, 4H), 4.21 (dd, J=12.3, 5.6 Hz, 2H),4.03-3.96 (m, 4H), 2.40-2.21 (m, 16H), 1.17-1.04 (m, 24H). ¹³C NMR (101MHz, CDCl₃) δ 174.2 (2C), 173.4 (2C), 173.3 (2C), 173.1 (2C), 91.9 (2C),70.0 (4C), 68.5 (2C), 68.3 (2C), 61.7 (2C), 27.6 (2C), 27.5 (6C), 9.3(2C), 9.1 (6C). MALDI TOF-MS: Calc [M+Na]⁺: 813.80. Found: 813.80.

Trehalose Octaisobutyrate:

D-Trehalose dihydrate (2 g, 5.3 mmol) was suspended in 20 mL drypyridine under inert atmosphere (N₂) followed by addition of isobutyricanhydride (15.5 mL, 93.5 mmol, ˜2.2 eq pr. OH) and a catalytic amount ofDMAP (73.1 mg, 0.6 mmol, ˜0.1 eq). The reaction was conducted at 49° C.for 47 h, whereafter TLC (10% acetone, toluene, Rf product ˜0.6) showedthat the reaction was only close to completion. Additional isobutyricanhydride (1.93 mL, 11.6 mmol) was added, and the reaction was continuedfor an additional 14 hat 58° C., whereafter the reaction was completed.Then followed concentration in vacuuo and co-evaporation of toluene. Thecrude concentrate was dissolved in CHCl₃ (100 mL) and washed with NaHCO₃(aq) (3×100 mL) and water (2×100 mL). The organic phase was dried withMgSO₄ (s), filtered, concentrated under reduced pressure and dried invacuuo. Yield: 4.3 g (91%). ¹H NMR (400 MHz, CDCl₃) δ 5.55 (t, J=9.8 Hz,2H), 5.36 (d, J=3.8 Hz, 2H), 5.10 (t, J=9.9 Hz, 2H), 5.03 (dd, J=10.1,3.8 Hz, 2H), 4.08 (m, 4H), 3.91 (ddd, J=10.4, 5.5, 2.1 Hz, 2H),2.63-2.52 (m, 4H), 2.48 (m, 4H), 1.17 (m, 24H), 1.13-1.07 (m, 24H). ¹³CNMR (101 MHz, CDCl₃) δ 176.7 (2C), 175.9 (2C), 175.7 (2C), 175.4 (2C),90.5 (2C), 70.2 (2C), 69.8 (2C), 68.6 (2C), 68.0 (2C), 61.6 (2C), 34.1(2C), 34.0 (4C), 33.9 (2C), 19.1 (2C), 19.0 (8C), 18.9 (4C), 18.8(2C).MALDI TOF-MS: Calc [M+Na]⁺: 926.02. Found: 925.97.

Maltose Esters: β-Maltose Octaacetate:

D-Maltose monohydrate (2 g, 5.6 mmol) was suspended in 20 mL drypyridine under inert atmosphere (N₂) followed shortly hereafter byaddition of acetic anhydride (9.5 mL, 100.5 mmol, ˜2.3 eq pr. OH) and acatalytic amount of DMAP (73.1 mg, 0.6 mmol , ˜0.1 eq). The reaction wasconducted at 49° C. for 47 h whereafter TLC (20% acetone, toluene, Rfproduct ˜0.4) showed that the reaction was completed. Then followedconcentration in vacuuo and co-evaporation with toluene. The crudeconcentrate was dissolved in CHCl₃ (100 mL) and washed with NaHCO₃ (aq)(3×100 mL) and water (2×100 mL). The organic phase was then dried withMgSO₄ (s), filtered and concentrated under reduced pressure. The pureβ-anomer was isolated by rechrystallization from isopropanol. Yield: 3.1g (82%). ¹H NMR (400 MHz, CDCl₃) δ 5.74 (d, J=8.1 Hz, 1H), 5.40 (d,J=4.0 Hz, 1H), 5.35 (dd, J=10.5, 9.5 Hz, 1H), 5.29 (t, J=8.9 Hz, 1H),5.05 (t, J=9.9 Hz, 1H), 4.97 (dd, J=9.2, 8.1 Hz, 1H), 4.85 (dd, J=10.5,4.0 Hz, 1H), 4.45 (dd, J=12.3, 2.5 Hz, 1H), 4.24 (t, J=3.9 Hz, 1H), 4.21(t, J=3.8 Hz, 1H), 4.07-4.00 (m, 2H), 3.93 (ddd, J=10.3, 3.8, 2.3 Hz,1H), 3.83 (ddd, J=9.6, 4.4, 2.5 Hz, 1H), 2.13 (s, 3H), 2.10 (s, 6H),2.04 (s, 3H), 2.02 (s, 3H), 2.01 (2×s, 6H), 2.00 (s, 3H). ¹³C NMR (101MHz, CDCl₃) δ 170.7, 170.6 (2C), 170.2, 170.0, 169.7, 169.6, 168.9,95.8, 91.4, 75.4, 73.1, 72.5, 71.1, 70.1, 69.4, 68.7, 68.1, 62.6, 61.6,21.00, 20.9, 20.8 (2C), 20.7 (4C). MALDI-TOF-MS: Calc [M+Na]⁺: 701.59.Found: 701.38.

β-Maltose Octapropionate:

D-Maltose monohydrate (2 g, 5.6 mmol) was suspended in 20 mL drypyridine under inert atmosphere (N₂) followed shortly hereafter byaddition of propionic anhydride (12.5 mL, 97.5 mmol, ˜2.2 eq pr. OH) anda catalytic amount of DMAP (68.9 mg, 0.56 mmol , ˜0.1 eq). The reactionwas conducted for 24 h at 48° C. and for an additional 16 h at 40° C.,whereafter TLC (10% acetone, toluene, Rf product ˜0.4) showed that thereaction was completed. Then followed concentration in vacuuo andco-evaporation with toluene. The concentrate was dissolved in CHCl₃ (100mL) and washed with NaHCO₃ (aq) (3×100 mL) and water (2×100 mL). Theorganic phase was dried with MgSO₄ (s), filtered and concentrated underreduced pressure. The pure β-anomer was isolated by rechrystallizationfrom isopropanol. Yield: 3.6 g (82%). ¹H NMR (400 MHz, CDCl₃) δ 5.75 (d,J=8.2 Hz, 1H), 5.41-5.33 (m, 2H), 5.30 (t, J=9.0 Hz, 1H), 5.08 (t, J=9.9Hz, 1H), 4.98 (dd, J=9.3, 8.2 Hz, 1H), 4.87 (dd, J=10.5, 4.0 Hz, 1H),4.45 (dd, J=12.3, 2.6 Hz, 1H), 4.25 (t, J=4.5 Hz, 1H), 4.22 (t, J=4.6Hz, 1H), 4.09-3.97 (m, 2H), 3.93 (ddd, J=10.3, 3.7, 2.1 Hz, 1H), 3.84(ddd, J=9.7, 4.4, 2.6 Hz, 1H), 2.43-2.20 (m, 16H), 1.17-1.03 (m,24H).¹³C NMR (101 MHz, CDCl₃) δ 174.1, 174.0 (2C), 173.4 (2C), 173.1,173.0, 172.4, 95.8, 91.4, 76.8, 75.3, 73.2, 72.2, 71.0, 69.9, 69.4,68.8, 67.8, 62.5, 61.4, 27.6 (2C), 27.5 (3C), 27.4 (2C), 27.3, 9.3, 9.1(4C), 8.9, 8.8 (2C). MALDI-TOF-MS: Calc [M+Na]⁺: 813.80. Found: 813.70.

α,β-Maltose Octapropionate:

D-Maltose monohydrate (2 g, 5.6 mmol) was suspended in 20 mL drypyridine under inert atmosphere (N₂) followed shortly hereafter byaddition of propionic anhydride (12.5 mL, 97.5 mmol, ˜2.2 eq pr. OH) anda catalytic amount of DMAP (70 mg, 0.57 mmol , ˜0.1 eq). The reactionwas conducted for 43 h at 48° C. and, whereafter TLC (10% acetone,toluene, Rf products ˜0.35) showed that the reaction was completed. Thenfollowed concentration in vacuuo and co-evaporation with toluene. Theconcentrate was dissolved in CHCl₃ (100 mL) and washed with NaHCO₃ (aq)(3×100 mL) and water (2:100 mL). The organic phase was dried with MgSO₄(s), filtered and concentrated under reduced pressure to give a whitesolid. Yield: 3.3 g (76%) (mixture of anomers, ˜4% alpha and ˜96%beta).¹H NMR (400 MHz, Chloroform-d) δ 6.25 (d, J=3.7 Hz, 0.04H, H-1 α),5.75 (d, J=8.2 Hz, 1H, H-1β), 5.53 (dd, J=10.1, 8.5 Hz, 0.04H),5.40-5.33 (m, 2H), 5.30 (t, J=9.0 Hz, 1H), 5.08 (t, J=9.9 Hz, 1H), 4.98(dd, J=9.3, 8.2 Hz, 1H), 4.87 (dd, J=10.5, 4.1 Hz, 1H), 4.45 (dd,J=12.2, 2.6 Hz, 1H), 4.25 (t, J=4.5 Hz, 1H) 4.22 (t, J=4.6 Hz, 1H), 4.12(m, 0.04 H), 4.09-3.98 (m, 2H), 3.93 (ddd, J=10.1, 3.7, 2.1 Hz, 1H),3.84 (ddd, J=9.6, 4.4, 2.6 Hz, 1H), 2.47-2.18 (m, -17H), 1.19-1.02 (m,˜25H). MALDI-TOF-MS: Calc [M+Na]⁺: 813.80. Found: 813.70.

β-Maltose Octaisobutyrate:

D-Maltose monohydrate (2 g, 5.6 mmol) was suspended in 20 mL drypyridine under inert atmosphere (N₂) followed by addition of isobutyricanhydride (16.2 mL, 97.7 mmol, -2.2 eq pr. OH) and a catalytic amount ofDMAP (68 mg, 0.56 mmol, 0.1 eq). The reaction was conducted under inertatmosphere at 48° C. for 24 h, and for an additional 17 h at 40° C.,whereafter TLC (10% acetone, toluene, Rf product ˜0.5) showed that thereaction was completed. Then followed concentration in vacuuo andco-evaporation with toluene. The concentrate was dissolved in CHCl₃ (100mL) and washed with NaHCO₃ (aq) (3×100 mL) and water (2×100 mL). Theorganic phase was then dried with MgSO₄ (s), filtered and concentratedunder reduced pressure. The pure β-anomer was isolated byrechrystallization from isopropanol. Yield: 4.5 g (89%). ¹H NMR (400MHz, CDCl₃) δ 5.74 (d, J=8.0 Hz, 1H), 5.40 (t, J=9.9 Hz, 1H), 5.36-5.26(m, 2H), 5.12 (t, J=9.8 Hz, 1H), 5.01 (dd, J=9.1, 8.0 Hz, 1H), 4.89 (dd,J=10.4, 4.0 Hz, 1H), 4.49 (dd, J=12.0, 2.7 Hz, 1H), 4.27 (dd, J=12.1,4.7 Hz, 1H), 4.20 (dd, J=12.5, 4.0 Hz, 1H), 4.11-3.99 (m, 2H), 3.96(ddd, J=10.4, 3.9, 2.0 Hz, 1H), 3.85 (ddd, J=9.6, 4.7, 2.7 Hz, 1H),2.66-2.38 (m, 8H), 1.21-1.06 (m, 48H). ¹³C NMR (101 MHz, CDCl₃) δ 176.8,176.6, 176.2, 175.8, 175.5, 175.4, 175.3, 175.0, 100.1, 95.2, 91.4,75.0, 73.3, 71.6, 70.7, 69.9, 69.3, 68.9, 67.6, 62.3, 61.5, 34.1, 34.0(3C), 33.9 (3C), 33.8, 19.3, 19.2, 19.1 (2C), 19.0 (4C), 18.9 (4C),18.7, 18.5 (2C), 18.4.MALDI TOF-MS: Calc [M+Na]⁺: 926.02. Found: 925.96.

Lactose Esters: α,β-Lactose Octaacetate:

β-Lactose (10 g, 29.2 mmol) was suspended in dry pyridine (100 mL) underinert atmosphere (N₂). Hereafter, Ac₂O (48.5 mL, 514 mmol, ˜2.2 eq pr.OH) was carefully added, followed by a catalytic amount of DMAP (357 mg,2.9 mmol, 0.1 eq). The reaction was heated to 48° C. and continued for24 h, then the reaction was cooled down to r.t. and continued foranother 24 h, whereafter TLC (25% acetone, toluene, Rf a anomer: ˜0.3,Rf β anomer: ˜0.35) showed that the reaction was completed. The reactionwas then concentrated in vacuuo and co-evaporated with toluene. Theconcentrate was dissolved in CHCl₃ (150 mL) and washed with NaHCO₃ (aq)(3×150 mL) and water (2×150 mL). The organic phase was dried with MgSO₄(s), filtered, concentrated under reduced pressure and dried in vacuuoresulting in an amorphous glass. Yield: 18.6 g (93.7% yield) (mixture ofanomers: ˜30% α and ˜70% β).¹H-NMR: (400 MHz, Chloroform-d) δ 6.24 (d,J=3.7 Hz, 0.4H, H-1 α), 5.66 (d, J=8.3 Hz, 1H, H-1 β), 5.44 (dd, 10.28,9.53 Hz, 0.4 H), 5.37-5.31 (m, 2H), 5.23 (t, J=9.1 Hz, 1H), 5.15-5,00(m, 3H), 4.99-4.91 (m, 2H), 4.50-4.41 (m, 3H), 4.17-4.05 (m, 4H), 3.99(ddd, J=10.2, 4.3, 2.1 Hz, 0.4H, H5 α), 3.91-3.78 (m, 3H), 3.75 (ddd,J=9.9, 4.8, 2.0 Hz, 1H, H5 β), 2.19-1.93 (singlets, ˜32 H, CH₃acetyls).MALDI TOF-MS: Calc [M+Na]⁺: 701.59. Found: 701.51.

α,β-Lactose Octapropionate:

β-Lactose (5 g, 14.6 mmol) was suspended in dry pyridine (50 mL) underinert atmosphere (N₂). Hereafter, propionic anhydride (33.5 mL, 257.4mmol, 2.2 eq pr. OH) was carefully added, followed by a catalytic amountof DMAP (181.3mg, 1.48 mmol, 0.1 eq). The reaction was heated to 60° C.and continued for 32 h, whereafter TLC (10% acetone, toluene, Rf αanomer: ˜0.35, Rf β anomer: ˜0.4) showed that the reaction wascompleted. The reaction was then concentrated in vacuuo andco-evaporated with toluene. The concentrate was dissolved in CH₂Cl₂ (150mL) and washed with 10% HCl (aq) (2×150 mL), then NaHCO₃ (aq) (2×100 mL)and water (2×200 mL).). The organic phase was dried with MgSO₄ (s),filtered, concentrated under reduced pressure and dried in vacuuoresulting in an amorphous glass. Yield: 9.7 g (84%) (mixture of anomers:—30% α and —70% β). ¹H-NMR (400 MHz, Chloroform-d) δ 6.26 (d, J=3.7 Hz,0.4H, H1-α), 5.68 (d, J=8.3 Hz, 1H, H-1 β), 5.47 (dd,10.3, 9.2 Hz,0.4H), 5.38-5.33 (m, 2H), 5.26 (t, J=9.2 Hz, 1H), 5.15 -5.00 (m, 3H),5.02-4.91 (m, 2H), 4.49-4.41 (m, 3H), 4.15-4.03 (m, 4H), 3.98 (ddd,J=10.1, 3.9, 1.8 Hz, 0.4 H, H5 α), 3.91-3.77 (m, 3H), 3.73 (ddd, J=9.9,4.6, 2.0 Hz, 1H, H5 β), 2.47-2.15 (m, ˜23H), 1.19-0.99 (m, ˜34H). MALDITOF-MS: Calc [M+Na]⁺: 813.80. Found: 813.42.

α,β-Lactose Octaisobutyrate:

β-Lactose (10 g, 29.2 mmol) was suspended in dry pyridine (100 mL) underinert atmosphere (N₂). Hereafter, isobutyric anhydride (85 mL, 512.6mmol, 2.2 eq. pr. OH) was carefully added, followed by a catalyticamount of DMAP (357 mg, 2.9 mmol , 0.1 eq). The reaction was heated to55° C. and continued for 36 h, whereafter the reaction was cooled downto r.t. and continued for another 24 h, whereafter TLC (10% acetone,toluene, Rf α anomer: ˜0.6, Rf β anomer: ˜0.65) showed that the reactionwas completed. The reaction was then concentrated in vacuuo andco-evaporated with toluene. The concentrate was dissolved in CHCl₃ (150mL) and washed with NaHCO₃ (aq) (3×150 mL) and water (2×150 mL). Theorganic phase was dried with MgSO₄ (s), filtered, concentrated underreduced pressure and dried in vacuuo resulting in an amorphous glass.Yield: 23.6 g (89,5%) (mixture of anomers: ˜30% α and ˜70% β). ¹H NMR(400 MHz, Chloroform-d) δ 6.26 (d, J=3.8 Hz, 0.4H, H-1β), 5.68 (d, J=8.3Hz, 1H, H-1β), 5.48 (dd, J=10.3, 9.3 Hz, 0.4 H), 5.40-5.34 (m, 2H), 5.27(t, J=9.5 Hz, 1H), 5.18-5.00 (m, 3H), 5.03-4.91 (m, 2H), 4.50-4.41 (m,3H), 4.24-4.02 (m, ˜4H), 3.95 (ddd, J=10.1, 3.8, 1.7 Hz, 0.4H, H5 α),3.91-3.80 (m, 3H), 3.70 (ddd, J=9.9, 4.5, 2.0 Hz, 1H, H5 β), 2.70-2.32(m, ˜11H), 1.26-1.01 (m, ˜68 H). MALDI TOF-MS: Calc [M+Na]⁺: 926.02.Found: 925.70.

Raffinose Esters: Raffionse Undecaacetate:

D-Raffinose pentahydrate (2 g, 3.4 mmol) was suspended in dry pyridine(20 mL) under inert atmosphere (N₂). Hereafter, acetic anhydride (6 mL,63.5 mmol, ˜1.7 eq pr. OH) was added followed by a catalytic amount ofDMAP (41 mg, 0.3 mmol, ˜0.1 eq). The reaction was heated to 48° C. andcontinued for 46 h where TLC (20% acetone, toluene, Rf product ˜0.3)showed that the reaction was completed. The reaction was concentrated invacuuo and co-evaporated with toluene. The concentrate was dissolved inCHCl₃ (100 mL) and washed with NaHCO₃ (aq) (3×100 mL) and water (2×100mL). The organic phase was dried with MgSO₄ (s), filtered, concentratedunder reduced pressure and dried in vacuuo. Yield: 2.9 g (88.7%). ¹H NMR(400 MHz, CDCl₃) δ 5.65 (d, J=3.6 Hz, 1H), 5.50-5.43 (m, 3H), 5.36-5.31(m, 1H), 5.30 (d, J=3.4 Hz, 1H), 5.13-5.08 (m, 2H), 5.07 (d, J=3.7 Hz,1H), 5.00 (dd, J=10.4, 9.4 Hz, 1H), 4.76 (dd, J=10.4, 3.6 Hz, 1H),4.41-4.22 (m, 6H), 4.22-4.10 (m, 2H), 4.03 (dd, J=11.3, 7.0 Hz, 1H),3.72 (dd, J=11.1, 6.1 Hz, 1H), 3.52 (dd, J=11.0, 2.0 Hz, 1H), 2.17 (s,3H), 2.14 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H), 2.11 (s, 3H), 2.10 (s,6H), 2.05 (s, 6H), 2.01 (s, 3H), 1.95 (s, 3H).¹³C NMR (101 MHz, CDCl₃) δ170.7 (2C), 170.6, 170.4, 170.3 (2C), 170.2 (2C), 169.8, 169.7, 169.6,105.0, 96.0, 90.2, 80.1, 76.5, 76.0, 70.7, 69.6, 69.4, 68.9, 68.4 (2C),67.5, 66.5, 66.1, 63.8, 62.0 (2C), 20.9 (4C), 20.8 (5C), 20.7 (2C).MALDITOF-MS: Calc [M+Na]⁺: 989.84. Found: 989.91.

Raffinose Undecapropionate:

D-Raffinose pentahydrate (2 g, 3.4 mmol) was suspended in dry pyridine(20 mL) under inert atmosphere (N₂). Hereafter, propionic anhydride (8mL, 62.4 mmol, ˜1.7 eq pr. OH) was carefully added followed by acatalytic amount of DMAP (46 mg, 0.4 mmol, ˜0.1 eq). The reaction washeated to 48° C. and continued for 42 h where TLC (10% acetone, toluene,Rf product ˜0.4) showed that the reaction was completed. The reactionwas concentrated in vacuuo and co-evaporated with toluene. Theconcentrate was dissolved in CHCl₃ (100 mL) and washed with NaHCO₃ (aq)(3×100 mL) and water (2×100 mL). The organic phase was dried with MgSO₄(s), filtered, concentrated under reduced pressure and dried in vacuuo.Yield: 3.3 g (86.7%). ¹H NMR (400 MHz, CDCl₃) δ 5.61 (d, J=3.6 Hz, 1H),5.52-5.41 (m, 3H), 5.39-5.30 (m, 2H), 5.15-5.04 (m, 3H), 4.82 (dd,J=10.4, 3.7 Hz, 1H), 4.43-4.22 (m, 6H), 4.21-4.01 (m, 3H), 3.73 (dd,J=11.3, 5.2 Hz, 1H), 3.54 (dd, J=11.3, 1.9 Hz, 1H), 2.50-2.17 (m, 22H),1.18-1.03 (m, ˜33H).¹³C NMR (101 MHz, CDCl₃) δ 174.2, 174.1, 174.0,173.8, 173.6 (4C), 173.2, 173.1, 173.0, 104.6, 96.4, 90.3, 79.7, 76.0,75.5, 70.3, 69.7 (2C), 68.5, 68.2 (2C), 67.7, 66.5, 66.0, 63.8, 62.4,61.7, 27.6 (2C), 27.5 (5C), 27.4 (2C), 27.3, 27.2, 9.4, 9.3, 9.2 (2C),9.1 (2C), 9.0 (5C). MALDI TOF-MS: Calc [M+Na]⁺: 1144.13. Found: 1144.18.

Raffinose Undecaisobutyrate:

D-Raffinose pentahydrate (2 g, 3.4 mmol) was suspended in dry pyridine(20 mL) under inert atmosphere (N₂). Hereafter, isobutyric anhydride (10mL, 60.3 mmol, ˜1.6 eq pr. OH) was carefully added followed by acatalytic amount of DMAP (47 mg, 0.4 mmol, ˜0.1 eq). The reaction washeated to 48° C. and continued for 43 h where TLC (10% acetone, toluene,Rf product ˜0.6) showed that the reaction was completed. The reactionwas then concentrated in vacuuo and co-evaporated with toluene. Theconcentrate was dissolved in CHCl₃ (100 mL) and washed with NaHCO₃ (aq)(3×100 mL) and water (2×100 mL). The organic phase was dried with MgSO₄(s), filtered, concentrated under reduced pressure and dried in vacuuo.Yield: 3.6 g (84.3%). ¹H NMR (400 MHz, CDCl₃) δ 5.58-5.44 (m, 4H),5.49-5.38 (m, 1H), 5.42-5.29 (m, 1H), 5.28 (t, J=9.8 Hz, 1H), 5.18-5.07(m, 2H), 4.89 (dd, J=10.4, 3.6 Hz, 1H), 4.41-4.30 (m, 1H), 4.31-4.14 (m,4H), 4.11-3.99 (m, 4H), 3.75 (dd, J=11.7, 3.4 Hz, 1H), 3.58 (dd, J=11.8,1.9 Hz, 1H), 2.71-2.34 (m, 11H), 1.24-1.08 (m, ˜66H). ¹³C NMR (101 MHz,CDCl₃) δ 176.6 (2C), 176.5, 176.1 (3C), 176.0, 175.9, 175.8, 175.5,175.1, 103.6, 97.0, 90.0, 78.7, 75.3, 74.6, 70.1, 69.8, 69.6, 68.1, 67.8(2C), 67.7, 66.6, 65.9, 64.2, 62.9, 61.4, 34.2, 34.0 (5C), 33.9 (4C),33.8, 19.3 (2C), 19.1 (3C), 19.0 (7C), 18.9 (6C), 18.8, 18.7, 18.5,18.4. MALDI TOF-MS: Calc [M+Na]⁺: 1298.43. Found: 1298.46.

Synthesis of α,β Lactose Acetate:Propionate 1:1 Regioisomers

Lactose (10 g, 29.2 mmol) was suspended under inert atmosphere in ˜120mL dry pyridine and cooled to 0° C. Hereafter, a mixture of of aceticanhydride (16.5 mL,175.3 mmol, ˜6 eq.) and propionic anhydride (22.5 mL,175.2 mmol, ˜6 eq.) was added dropwise through a separatory funnel undervigorous stirring. Hereafter, the reaction was allowed to slowly re-heatto r.t. over ˜30 min. Then, a catalytic amount of DMAP (˜357 mg, 2.9mmol, ˜0.1 eq) was added, and the reaction was continued at 48° C.overnight under inert atmosphere. Then MALDI TOF-MS confirmed that thereaction was done. Hereafter followed evaporation of the solvent andanhydride with co-evaporation of toluene (2×20 mL) to remove theresidual anhydride. The final purification consisted of dissolution inCHCl₃ (100 mL) and washing with NaHCO₃ (aq) (4×100 mL), water (1×100 mL)and brine (1×100 mL). The organic phase was then dried with MgSO₄ (s),filtered, concentrated under reduced pressure and dried in vacuuo.Yield: 15.2g (71%) (calculated after the expected weight of overall ˜1:1acetate:propionate mixture in the resulting product (confirmed by¹H-NMR)), ˜75% β and ˜25% α (from ¹H-NMR). ¹H-NMR (400 MHz,Chloroform-d): δ 6.28-6.23 (m, 2H, H-1α), 5.71-5.63 (m, 6H, H-1β),5.52-5.41 (m, 2H), 5.40-5.31 (m, 12H), 5.31-5.19 (m, 6H), 5.16-4.88 (m,˜15H), 4.52-4.40 (m, ˜16H), 4.19-4.03 (m, ˜28H), 4.03-3.94 (m, 2H),3.91-3.79 (m, ˜18H), 3.80-3.70 (m, 6H), 2.50-2.18 (m, ˜48H, CH₂propionate), 2.15-1.92 (m, ˜72H, CH₃ acetate), 1.27-0.93 (m, ˜72H, CH₃propionate). MALDI TOF-MS: Compound with 7 acetyl and 1 propyl [M+Na]⁺:Calc.: 715.62. Found: 715.7. Compound with 6 acetyl +2 propyl [M+Na]⁺:Calc.: 729.65. Found: 729.81. Compound with 5 acetyl +3 propyl [M+Na]⁺:Calc.: 743.67. Found: 743.85. Compound with 4 acetyl +4 propyl [M+Na]⁺:Calc.: 757.70. Found: 757.88. Compound with 3 acetyl +5 propionyl[M+Na]⁺: Calc: 771.73. Found: 771.9. Compound with 6 propionyl +2 acetyl[M +Na]⁺. Calc: 785.76. Found: 785.93.

Regioisomer Trehalose Synthesis Synthesis of TrehaloseAcetate:Propionate 3:1 and 2:1 Regioisomers

Synthesis a): D-Trehalose dihydrate (5 g, 13.2 mmol) was suspended underinert atmosphere in 50 mL dry pyridine followed shortly hereafter byaddition of acetic anhydride (15 mL, 159 mmol, ˜12 eq.) and propionicanhydride (10 mL, 78 mmol, ˜6 eq.) roughly in a 2:1 relationship (aceticanhydride was added first, shortly hereafter, propionic anhydride wasadded). Hereafter a catalytic amount of DMAP (˜166 mg, 1.4 mmol, ˜0,1eq) was added. The reaction was conducted under inert atmosphere at r.t.for 1.5 days. Then TLC (20% acetone, toluene) showed that the reactionwas done (approximately 5 spots from rf ˜0.3-0.5). Then followedevaporation of the solvent and anhydride, with co-evaporation of toluene(2×20 mL) to remove the residual anhydride. The final purificationconsisted of dissolution in CHCl₃ (100 mL) and washing with NaHCO₃ (aq)(4×100 mL), water (2×100 mL) and brine (1×100 mL). The organic phase wasthen dried with MgSO₄ (s), filtered, concentrated under reduced pressureand dried in vacuuo. Yield: 6,4 g (˜69%, calculated after the expectedweight of overall ˜3:1 acetate:propionate mixture in the resultingproduct (confirmed by ¹H-NMR)). ¹H-NMR (400 MHz, Chloroform-d): δ5.54-5.44 (m, 10H, H-1 and H-1′), 5.32-5.25 (m, 10H), 5.10-4.99 (m,20H), 4.23 (m, 10H), 4.08-3.95 (m, 20H), 2.41-2.21 (m, ˜20H, CH₂propionate), 2.11-1.97 (m, ˜90H, CH₃ Acetate), 1.19-1.05 (m, ˜30H, CH₃propionate). MALDI TOF-MS: Uniformly acetylated compound [M+Na]⁺: Calc.:701.59. Found: 701.61. Compound with 7 acetyl groups and one propionylgroup [M+Na]⁺: Calc.: 715.62. Found: 715.66. Compound with 6 acetylgroups and two propionyl groups [M+Na]⁺: Calc.: 729.65. Found: 729.70.Compound with 5 acetyl groups and three propionyl groups: [M+]⁺: Calc.:743.67. Found: 743.74. Compound with 4 acetyl groups and 4 propionylgroups: [M+Na]⁺: Calc.: 757.70. Found: 757.75.

Synthesis b): D-Trehalose dihydrate (5 g, 13,2 mmol) was suspended underinert atmosphere in 50 mL dry pyridine followed shortly hereafter byaddition of acetic anhydride (11 mL, 116.6 mmol, 8.8 eq) and propionicanhydride (15 mL, 116.9 mmol, ˜8.9 eq) in a ˜1:1 relationship (aceticanhydride was added first, shortly after propionic anhydride was added).Hereafter a catalytic amount of DMAP (˜165 mg, 1.4 mmol, ˜0.1 eq) wasadded. The reaction was conducted under inert atmosphere at r.t. for 1.5days. Then TLC (20% acetone, toluene) showed that the reaction was done(approximately ˜6 spots from rf ˜0.3-0.6). Then followed evaporation ofthe solvent and anhydride with co-evaporation of toluene (2×20 mL) toremove the residual anhydride. The final purification consisted ofdissolution in CHCl₃ (100 mL) and washing with NaHCO₃ (aq) (4×100 mL),water (2×100 mL) and brine (1×100 mL). The organic phase was then driedwith MgSO₄ (s), filtered, concentrated under reduced pressure and driedin vacuuo. Yield: 6.9 g (˜73% yield, calculated after overall ˜2:1Acetate:propionate mixture in the resulting product (confirmed by¹H-NMR)). ¹H-NMR (400 MHz, Chloroform-d): δ 5.54-5.45 (m, 12H. H-1 andH-1′), 5.32-5.25 (m, 12H), 5.10-4.99 (m, 24H), 4.27-4.17 (m, 12H),4.09-3.95 (m, 24H), 2.40-2.21 (m, 32H, CH₂ propionate), 2.11-1.97 (m,96H, CH₃ acetate), 1.18-1.04 (m, 48H, CH₃ propionate). MALDI TOF-MS:Uniformly acetylated compound [M+Na]⁺: Calc.: 701.59. Found: 701.61.Compound with 7 acetyl groups and one propionyl group [M+Na]⁺: Calc.:715.62. Found: 715.68. Compound with 6 acetyl groups and two propionylgroups [M+Na]⁺: Calc.: 729.65. Found: 729.73. Compound with 5 acetylgroups and three propionyl groups: [M+Na]⁺: Calc.: 743.67. Found:743.77. Compound with 4 acetyl groups and 4 propionyl groups: [M+Na]⁺:Calc.: 757.70. Found: 757.79. Compound with 3 acetyl groups and 5propionyl groups: [M+Na]⁺: Calc.: 771.73. Found: 771.81.

EXAMPLE II Gel Formation

The gel-forming properties of the synthesized esters containing onlysmall percentages of organic solvents and/or triglycerides wereinspected in the following experiments

Gels Formulated with EtOH:

—210 mg of the following sugar ester formulations: α,β Lactoseoctaacetate: α,β Lactose octaisobutyrate 5:1, α,β Lactose octaacetate:α,β Lactose octaisobutyrate 2:1, α,β Lactose octaacetate: α,β Lactoseoctaisobutyrate 1:1, α,β Lactose octaacetate: α,β Lactose octapropionate1:1, α,β Lactose octaacetate: α,β Lactose octapropionate 1:5, α,βLactose octaacetate: α,β Lactose octapropionate 1:3, α,β Lactoseoctapropionate: α,β Lactose octaisobutyrate 1:1, α,β Lactoseoctaacetate: α,β Lactose octaisobutyrate 1:5 , α,β Lactoseoctapropionate, α,β Lactose octaisobutyrate: α,β Lactose octaacetate0.5:0.5:5, α,β Lactose octaisobutyrate: α,β Lactose octaacetate 3:1,Trehalose octaacetate:Trehalose octapropionate 1:1, Trehaloseoctapropionate, Trehalose octaisobutyrate, Raffinoseundecaacetate:Raffinose undecapropionate 1:1, Raffinoseundecaisobutyrate, β-maltose octaisobutyrate and α,β-D-glucosaminepentapropionate were mixed with 20 wt % EtOH by heating to ˜37° C.,vortexing and ultrasonication. ˜50-80 uL of the resulting formulationswere then injected into 2 mL of PBS buffer using 25 G needles. All ofthe solutions formed gels upon injection (examples shown in FIG. 1).

Gels Rormulated with DMSO, NMP or Propylene Carbonate:

˜210 mg of the following sugar ester formulations: α,β Lactoseoctaacetate, α,β lactose octapropionate, α,β Lactose octaacetate:α,βlactose octapropionate 1:1, α,β lactose octaisobutyrate, α,β maltoseoctapropionate, β maltose octapropionate, α-D-glucosaminepentapropionate, α, β-D-glucosamine pentapropionate, β maltoseoctapropionate: α-D-glucosamine pentapropionate 1:1 and α-D-glucosaminepentaisobutyrate were mixed with 20 wt % NMP or DMSO by heating to ˜37°C., vortexing and ultrasonication. ˜50-60 uL of the resultingformulations were injected into PBS. With maltose octapropionate,glucosamine pentapropionate and lactose octaacetate alternative wt % ofsolvents were also tried (i.e. 25-40 wt % of the before mentionedsolvents). In all cases, formation of an amorphous solid (gel) was seen.In case of α,β -maltose propionate and α,β-D-glucosaminepentapropionate, injection into PBS and gel-formation are alsosuccessful when formulated with 35% and 20% propylene carbonate,respectively (examples shown in FIG. 1). Pure α-D-Glucosamine esters andhydrophilic maltose ester analogues have a tendency to form hardamorphous solids with some crystallinity after injection into PBS—soalthough ˜20wt % solvent is possible to inject with difficulty, gels ofthis type containing ˜25-35 wt % solvent are easier to handle. Although,pure acetylated esters such as lactose octaacetate are injectable in 20wt % DMSO or 20 wt % propylene carbonate, this occurs with difficultydue to high viscosity of the resulting formulation—˜30-40 wt % solvent(EtOH, DMSO/NMP or propylene carbonate) is more appropriate for forminginjectable gels of pure acetyl esters.

Gels Formulated with Triglyceride:

˜210 mg of α,β Lactose octaacetate: α,β Lactose octapropionate 1:1 orα,β Lactose octaisobutyrate were mixed with 2, 5 or 10 wt % glyceroltrioctanoate, 5% DMSO and EtOH was added to give 20wt % solvent in totalfor all formulations. In case of lactose octaisobutyrate, formulationscontaining 15 wt % glycerol trioctanoate and 5% DMSO, 30 wt % glyceroltrioctanoate and 5% NMP/DMSO or 40 wt % glycerol trioctanoate alone werealso made. The solutions were mixed by heating to ˜37° C., vortexing andultrasonication. ˜40-60 uL of the resulting formulations were injectedinto PBS. In all cases, formation of an amorphous solid (gel) was seen.In case of pure triglyceride used as “solvent”, the injected solid wasvery soft, transparant and could easily be manipulated in shape byshaking the vial, even 24 h after injection (example shown in FIG. 1).

EXAMPLE III In Vitro Release of Fluorophores

The different carbohydrate esters synthesized as described in Example I,were used hereafter in the release experiments. All other chemicals usedin the experiments were purchased from CCS Healthcare (absolute ethanol)and Sigma Aldrich (other chemicals) and were used as received from themanufacturer.

General experimental conditions: In vitro release kinetics of differentcompounds from carbohydrate ester formulations were examined afterinjection of small droplets of 75-80% gel forming carbohydrate, and 20%non-toxic water miscible solvent through 21-25 G hyperdermic needlesinto PBS buffer (2 mL). The experiments were kept at 37° C. and smallaliquots of PBS (10 μL) were removed at specific time intervals andreplaced with fresh buffer. The amount of released fluorophore wasdetermined by UV-vis spectroscopy on a Thermo Scientific Nano Drop 2000C spectrophotometer using standard curves with known concentrations.

Fluorophore: Isoniazide

˜204 mg of lactose isobutyrate or lactose acetate:lactose propionate(1:1) (80%) were mixed with 20% absolute EtOH and isoniazide (LogP˜−0.8)to give concentrations of ˜5 μg/μL in the gel. 50 and 80 μL of thelactose acetate:lactose propionate 1:1 gel and the lactose isobutyrategel respectively were injected into PBS. Cumulative release was measuredby UV-vis at 263 nm (see FIG. 2).

Fluorophore: Fluorescein Free Acid

˜204 mg of lactose isobutyrate or ˜231 mg of lactose acetate:lactosepropionate (1:1) (80%) were mixed with 20% absolute EtOH and fluoresceinfree acid (LogP-˜1.8) to give concentrations of ˜1.7 μg/μL in the gel.70 μL of each solution was injected into PBS. Cumulative release wasmeasured by UV-vis at 490 nm (see FIG. 3).

Fluorophore: Eosin Y

˜204 mg of lactose isobutyrate or lactose acetate:lactose propionate(1:1) (80%) were mixed with 20% absolute EtOH and Eosin Y (LogP ˜6.4) togive concentrations of ˜2.4 μg/μL in the gel. 50 and 80 μL of thelactose acetate:lactose propionate 1:1 gel and the lactose isobutyrategel respectively were injected into PBS. Cumulative release was measuredby UV-vis at 515 nm (see FIG. 4).

EXAMPLE IV In Vitro Release of Chemotherapeutics

The different carbohydrate esters synthesized as described in Example I,were synthesized and used hereafter in the release experiments. Allother chemicals used in the experiments were purchased from CCSHealthcare (absolute ethanol) and Sigma Aldrich (other chemicals) andwere used as received from the manufacturer.

General experimental conditions: In vitro release kinetics of differentcompounds from carbohydrate ester formulations were examined afterinjection of small droplets of 49-80% gel forming carbohydrate, 0-50%additive (PLA/PLGA/cellulose acetate butyrate (CAB)/glycerol ester) and20-30% non-toxic water miscible solvent through 21-25 G hyperdermicneedles into PBS buffer (2 mL). The experiments were kept at 37° C. andsmall aliquots of PBS (10 μL unless otherwise noted) were removed atspecific time intervals and replaced with fresh buffer. All percentagesgiven in gel-compositions are weight % (% w/w). The amount of releasedchemotherapeutics was determined by UV-vis spectroscopy on a ThermoScientific Nano Drop 2000 C spectrophotometer using standard curves withknown concentrations.

Chemotherapeutic: 5-fluorouracil

˜220 mg of lactose isobutyrate or lactose acetate:lactose propionate(1:1) (80%) were mixed with 20% DMSO containing 5-fluorouracil (5-FU) togive concentrations of ˜5 μg/μL in the gel. 50 μL of each solution wasinjected into PBS. Cumulative release was measured by UV-vis at 265 nm(see FIG. 5).

˜210 mg of lactose propionate (80%) were mixed with different solvents(20% DMSO, 20% NMP, 5% DMSO and 15% absolute EtOH or 5% NMP and 15%absolute EtOH) containing 5-FU to give an average concentration of ˜5μg/μL in the gels. ˜40-70 μL of each solution was injected into PBS.Cumulative release was measured by UV-vis at 265 nm (see FIG. 6).

˜224 mg of lactose propionate (75%) and 5% of different additives (PLGAMn 4000-15,000 or PLA Mn 10,000-18,000) were mixed with 5% DMSO and 15%EtOH containing 5-FU to give average concentrations of ˜5 μg/μL in thegels. 80 μL of both gels were injected into PBS. The gel-formulationcontaining no PLA was formulated according to FIG. 6 for 80% lactosepropionate containing 15% EtOH and 5% DMSO, and 40 μL of the gel wasinjected into PBS. Cumulative release was measured by UV-vis at 265 nm(see FIG. 7).

˜210 mg of trehalose isobutyrate, trehalose acetate:propionate 1:1,Raffinose isobutyrate and raffinose acetate:propionate 1:1 were mixedwith 15% EtOH and 5% DMSO containing 5-FU to give average concentrationsof ˜3 μg/μL in the gels. ˜70 μL of the formulations were injected intoPBS. Cumulative release was measured by UV-vis at 265 nm (FIG. 8).

˜170-210 mg of glucosamine isobutyrate, glucosamine propionate, maltoseisobutyrate and maltose propionate were mixed with different solventscontaining 5-FU. In case of the glucosamine esters, 20% DMSO was used,while maltose isobutyrate and maltose propionate were mixed with 15%EtOH and 30% propylene carbonate respectively with 5% DMSO containing5-FU to give average concentrations of ˜3 μg/μL in the gels. ˜20-70 μLof the formulations were injected into PBS. Cumulative release wasmeasured by UV-vis at 265 nm (see FIG. 9).

˜300 mg of lactose isobutyrate (80%) or lactose acetate:propionate 1:1was mixed with 2, 5 or 10% glycerol trioctanoate, 5% DMSO (containing5-FU) and EtOH to give a total of 20% solvent. This resulted in anaverage concentration of ˜10 μg/μL 5-FU in the gels. ˜40-50 μL of theformulations were injected into PBS. Aliquots of 1 mL buffer wereremoved at specific time intervals and replaced with clean buffer.Cumulative release was measured by UV-vis at 265 nm (see FIG. 10).

˜300 mg of lactose isobutyrate (65%) was mixed with 30% glyceroltrioctanoate and 5% DMSO or 5% NMP containing 5-FU. This resulted inaverage concentrations of ˜11 μg/μL 5-FU in the gels. ˜50 μL of theformulations were injected into PBS. Aliquots of 1 mL buffer wereremoved at specific time intervals and replaced with clean buffer.Cumulative release was measured by UV-vis at 265 nm (see FIG. 11).

Chemotherapeutic: Gemcitabine HCl

˜210 mg of lactose isobutyrate and ˜230 mg of lactose acetate:lactosepropionate (1:1) (80%) were mixed with 20% DMSO containing GemcitabineHCl to give concentrations of ˜5.5 μg/μL in the gels. 50 and 80 μL ofthe lactose acetate:lactose propionate 1:1 gel and the lactoseisobutyrate gel respectively were injected into PBS. Cumulative releasewas measured by UV-vis at 268 nm (see FIG. 12).

˜210 mg of maltose isobutyrate and glucosamine isobutyrate (80%) weremixed with 15% EtOH and 15% DMSO respectively, then 5% DMSO containingGemcitabine HCl was added to both to give concentrations of ˜1.4 μg/μLin the gels. ˜70 μL of each gel was injected into PBS. Cumulativerelease was measured by UV-vis at 268 nm (see FIG. 13).

˜210 mg of maltose isobutyrate and glucosamine isobutyrate were mixedwith 20% DMSO, whereas ˜210 mg of maltose propionate was mixed with 35%DMSO containing Gemcitabine HCl to give average concentrations of ˜2-3μg/μL in the gels. 50-60 μL of the formulations were injected into PBS.Cumulative release was measured by UV-vis at 268 nm (see FIGS. 14 and15).

Chemotherapeutic: Tirapazamine

˜210 mg of lactose isobutyrate and of lactose acetate were formulated asfollows: Lactose isobutyrate was mixed with either 15% EtOH or 15%glycerol trioctanoate, while lactose acetate was mixed with 30% EtOH toform an injectable gel. All gels were mixed with an additional ˜5% DMSOcontaining tirapazamine (LogP ˜−0.06) to give concentrations of ˜1 μg/μLin the gels. ˜20-70 μL of the gels were injected into PBS. Cumulativerelease was measured by UV-vis at 266 nm (see FIG. 16).

Immunotherapeutic: Resiquimod

˜300 mg of lactose acetate:propionate (1:1) was mixed with Resiquimod intBuOH and freeze-dried overnight (or until dry). Secondly, thecarbohydrate-drug matrix was mixed with 0, 2, 5,10, or 15% glyceroltrioctanoate, 10% propylene carbonate and 5, 8 o r 10% EtOH to give atotal of 20-30% solvent. This resulted in an average concentration of˜1.78 μg/μL Resiquimod in the gels. ˜50 μL of the formulations wasinjected into 2 mL PBS. Aliquots of 1 mL buffer were removed at specifictime intervals and replaced with clean buffer. Cumulative release wasmeasured by fluorescence spectroscopy (excitation: 330 nm, emission:355nm) (see FIG. 17a ).

˜300 mg of lactose acetate:propionate (1:1) was mixed with Resiquimod intBuOH and freeze-dried overnight (or until dry). Secondly, thecarbohydrate-drug matrix was mixed 2% PLGA 75:25 (Mw: 4.000-15.000 kDa)and with 0, 2, 5, 10, or 15% glycerol trioctanoate, 10% propylenecarbonate and 5, 8, or 10% EtOH to give a total of 20-30% solvent. Thisresulted in an average concentration of ˜1.78 μg/μL Resiquimod in thegels. ˜50 μL of the formulations was injected into 2 mL PBS. Aliquots of1 mL buffer were removed at specific time intervals and replaced withclean buffer. Cumulative release was measured by fluorescencespectroscopy (excitation: 330 nm, emission: 355nm) (see FIG. 17b ).

Immunotherapeutic: Imiquimod

˜300 mg of lactose acetate:propionate (1:1) was mixed with Imiquimod intBuOH and freeze-dried overnight (or until dry). Secondly, thecarbohydrate-drug matrix was mixed with 0, 2, or 5% glyceroltrioctanoate, 10% propylene carbonate and 5, 8 or 10% EtOH to give atotal of 20% solvent. This resulted in an average concentration of ˜2.6μg/μL Imiquimod in the gels. ˜50 μL of the formulations was injectedinto 2 mL PBS. Aliquots of 1 mL buffer were removed at specific timeintervals and replaced with clean buffer. Cumulative release wasmeasured by fluorescence spectroscopy (excitation: 330 nm, emission:355nm) (see FIG. 17c ).

˜300 mg of lactose acetate:propionate (1:1) was mixed with Imiquimod intBuOH and freeze-dried overnight (or until dry). Secondly, thecarbohydrate-drug matrix was mixed 2% PLGA 75:25 (Mw 4.000-15.000 kDa)and with 0, 2, or 5% glycerol trioctanoate, 10% propylene carbonate and5, 8 or 10% EtOH to give a total of 20-30% solvent. This resulted in anaverage concentration of ˜2.6 μg/μL Imiquimod in the gels. ˜50 μL of theformulations was injected into 2 mL PBS. Aliquots of 1 mL buffer wereremoved at specific time intervals and replaced with clean buffer.Cumulative release was measured by fluorescence spectroscopy(excitation: 330 nm, emission: 355nm) (see FIG. 17d ).

Chemotherapeutic: Gemcitabine

˜300 mg of lactose acetate:propionate 1:1 was mixed with 2, 5 or 10%glycerol trioctanoate, 5% DMSO (containing Gemcitabine HCl) and EtOH togive a total of 20% solvent. This resulted in an average concentrationof ˜9 μg/μL gemcitabine in the gels. ˜50 μL of the formulations wereinjected into PBS. Aliquots of 1 mL buffer were removed at specific timeintervals and replaced with clean buffer. Cumulative release wasmeasured by UV-vis at 268 nm (see FIG. 20)

Chemotherapeutic: Lomeguatrib

˜300 mg of lactose isobutyrate or lactose acetate:propionate 1:1 wasmixed with a lomeguatrib solution (in tBuOH/water) and freeze-driedovernight. The resultant carbohydrate-drug matrix was mixed with 40-50%triglyceride (glycerol trioctanoate (GTO) or glycerol trihexanoate(GTH)) along with either 5% EtOH or 0.25% cellulose acetate butyrate(CAB, Mn˜12000). This resulted in an average concentration of ˜72 μg/μLlomeguatrib in the gels. ˜50 μL of the formulations were injected intoPBS. Aliquots of 1 mL buffer were removed at specific time intervals andreplaced with clean buffer. Cumulative release was measured by UV-vis at249 nm (see FIG. 21). Chemotherapeutic: Tirapazamine

˜300 mg of lactose isobutyrate or lactose acetate:propionate 1:1 wasmixed with a tirapazamine solution (in tBuOH/water) and freeze-driedovernight. The resultant carbohydrate-drug matrix was mixed with 10-50%triglyceride (glycerol trioctanoate (GTO) or glycerol trihexanoate(GTH)) tuning the formulations with 5-15% propylene carbonate or 1-0.25%cellulose acetate butyrate (Mn ˜12000). This resulted in an averageconcentration of ˜35 μg/μL tirapazamine in the gels. ˜50 μL of theformulations were injected into PBS. Aliquots of 1 mL buffer wereremoved at specific time intervals and replaced with clean buffer.Cumulative release was measured by UV-vis at 266nm (see FIG. 22 a andb).

Chemotherapeutic: Temozolomide

˜300 mg of lactose isobutyrate or lactose acetate:propionate 1:1 wasmixed with a temozolomide solution (in tBuOH/water) and freeze-driedovernight. The resultant carbohydrate-drug matrix was mixed with 40-50%triglyceride (glycerol trioctanoate (GTO) or glycerol trihexanoate(GTH)) tuning the formulations with 5-10% propylene carbonate/ethanol or1-0.25% cellulose acetate butyrate (Mn ˜12.000). This resulted in anaverage concentration of ˜15 μg/μL temozolomide in the gels. ˜50 μL ofthe formulations were injected into NaOAc/AcOH buffer. Aliquots of 1 mLbuffer were removed at specific time intervals and replaced with cleanbuffer. Cumulative release was measured by UV-vis at 330nm (see FIG.23).

Chemotherapeutic: Methotrexate

˜300 mg of lactose isobutyrate or lactose acetate:propionate 1:1 wasmixed with a methotrexate solution (in tBuOH/water) and freeze-driedovernight. The resultant carbohydrate-drug matrix was mixed with 10-30%triglyceride (glycerol trioleate) tuning the formulations with 15-25%propylene carbonate in order to obtain the right viscosity forinjectability. This resulted in an average concentration of ˜32 μg/μLmethotrexate in the gels. ˜50 μL of the formulations were injected intoPBS. Aliquots of 1 mL buffer were removed at specific time intervals andreplaced with clean buffer. Cumulative release was measured by UV-vis at372 nm (see FIG. 24).

Chemotherapeutic: 5-FU

˜400 mg of lactose isobutyrate or lactose acetate:propionate 1:1 wasmixed with a 5-FU solution (in tBuOH/water) and freeze-dried overnight.The resultant carbohydrate-drug matrix was mixed with 40-50%triglyceride (glycerol trioctanoate (GTO) or glycerol trihexanoate(GTH)) tuning the formulations with 5-10% propylene carbonate/ethanol or1-0.25% cellulose acetate butyrate (Mn ˜12.000). This resulted in anaverage 5-FU concentration of ˜30 μg/μL 5-FU in the gels. ˜50 μL of theformulations were injected into PBS. Aliquots of 1 mL buffer wereremoved at specific time intervals and replaced with clean buffer.Cumulative release was measured by UV-vis at 265 nm (see FIG. 25 a andb).

˜400 mg of lactose isobutyrate or lactose acetate:propionate 1:1 wasmixed with a 5-FU solution (in tBuOH/water) and freeze-dried overnight.The resultant carbohydrate-drug matrix was mixed with a) 10-50%triglyceride (glycerol trioctanoate (GTO) or glycerol trihexanoate(GTH)) tuning the formulations with 5-10% propylene carbonate/ethanol or2-0.25% cellulose acetate butyrate (Mn ˜12.000) or b) 20-30% propylenecarbonate or ethanol, in case of EtOH with or without 2% PLGA (Mw4000-15000). This resulted in an average 5-FU concentration of ˜48 μg/μL5-FU in the gels. ˜50 μL of the formulations were injected into PBS.Aliquots of 1 mL buffer were removed at specific time intervals andreplaced with clean buffer. Cumulative release was measured by UV-vis at265 nm (see FIG. 26 a, b, c and d + FIG. 27 a, b, c and d).

˜400 mg of lactose acetate:propionate 1:1 or lactose acetate:propionateregioisomers or trehalose acetate:propionate regioisomers were mixedwith a 5-FU solution (in tBuOH/water) and freeze-dried overnight. Theresultant carbohydrate-drug matrix was mixed with a) 40-50% triglyceride(glycerol trihexanoate (GTH)) tuning the formulations with 5-10%propylene carbonate/ethanol or b) 30% ethanol and 2% PLGA (Mw4000-15000). This resulted in an average 5-FU concentration of ˜48 μg/μL5-FU in the gels. ˜50 μL of the formulations were injected into PBS.Aliquots of 1 mL buffer were removed at specific time intervals andreplaced with clean buffer. Cumulative release was measured by UV-vis at265 nm. (FIG. 28 a, b and c + FIG. 29).

EXAMPLE V In Vivo Gel Stability Evaluation

Formulations of lactose isobutyrate:X-SAIB (contrast agent): EtOH andDMSO with composition of 1)75:5:15:5, 2) 77,5:5:12,5:5 and 2) 80:5:10:5were prepared along with formulations of lactoseacetate:propionate(1:1):X-SAIB(contrast agent): EtOH and DMSO in75:5:15:5 ratio. All of the gel formulations were prepared with ˜0.7%0of Hoechst 33342, as model of a DNA binding drug. 25-30 uL of each gelwas injected into FaDu Head and Neck xenografts grown on the flank ofNMRI nude mice (groups of 4-8 mice were injected with each formulation).Release and gel-stability was monitored for a maximum of 5-6 days. 2-3mice were sacrificed at predetermined times (day 1, middle of theexperimental period and at the end of the experimental period). Thetumors were excised and snap-frozen with liquid N₂ to preserve the tumortissue for histological examination. Stability of the radiopaquegel-depots was evaluated by micro-CT imaging (see FIG. 18). Only thelactose isobutyrate gel was subjected to X-rays, to evaluate the effectof radiation on gel-stability. Neither radiation nor the biologicalconditions in the tumor tissue seemed to significantly affect the gelstability, as the shape and size stayed relatively uniform over time.Diffusion of Hoechst was evaluated by fluorescent imaging of the tumorcryo-sections (see FIG. 19). Imaging confirmed release of Hoechst intothe tumors, and showed distribution of the fluorophore across most ofthe tumor area over a period of 6 days.

EXAMPLE VI In Vivo Gel Efficacy Evaluation 30

Combination with Radiation Therapy

Lactose isobutyrate:GTO with composition 60:40 w/w % was prepared with22,4 μg/μL 5-fluoruracil. 25 μL gel (5-FU dose per mouse: 20 mg/kg) wasinjected intratumoral into Fadu Head and Neck xenograft tumors (averagetumor size: 150-200 mm3) subcutaneously grown on the flank of nude NMRImice, at a flow rate of 5 μl/minute. On day 1 after gel injection, thetumors were subjected to radiation therapy (4 times 5 Gy on day 1, 4, 7and 10). Each group consisted of 7-8 mice and the tumor growthprogression was monitored 3 times a week. The mice were euthanized oncetheir tumors had exceeded 1000 mm3. During the same period, weight ofindividual mice was monitored to observe the safety profile. (see FIG.30, a: tumor growth curve, b: survival curve).

1. A composition comprising non-water soluble carbohydrates, wherein at least 50% of the non-water soluble carbohydrates are carbohydrates selected from derivatives of lactose, maltose, trehalose, raffinose, glucosamine, galactosamine, lactosamine, or derivatives of disaccharides with at least two pyranose saccharide units, trisaccharides, tetrasaccharides, or mixtures thereof, and wherein the composition is a liquid before administration into the human or animal body and increases in viscosity by more than 1,000 centipoise (cP) after administration, for use as a medicament.
 2. The composition according to claim 1, for use as a controlled release system of one or more active pharmaceutical ingredients in a human or animal body.
 3. The composition according to claim 1, wherein the composition is a liquid before administration into the human or animal body that increases in viscosity by more than 10,000 centipoise (cP) after administration into the human or animal body.
 4. The composition according to claim 1, wherein the composition is a liquid before administration and has the ability to transform into a gel-like material after administration.
 5. The composition according to claim 1, wherein the composition becomes a solid after administration, such as a crystalline or amorphous solid.
 6. The composition according to claim 1, wherein an increase in viscosity after administration into the human or animal body is due to diffusion of a molecule out of the administered material and into surrounding tissue.
 7. The composition according to claim 1, wherein an increase in viscosity after administration into the human or animal body is due to diffusion of solvent-like molecules.
 8. The composition according to claim 1, wherein the non-water soluble carbohydrates are disaccharides with structures selected from:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ in formulae I, II and III are selected collectively from the group consisting of hydrogen, alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selected from the group consisting of hydrogen, alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; or wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are selected collectively from the group consisting of acetyl, isobutyryl or propionyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selected from the group consisting acetyl, isobutyryl or propionyl; and wherein both pure anomers and mixtures of α- and β-anomers of the above mentioned structural variations are claimed.
 9. The composition according to claim 1, wherein the non-water soluble carbohydrates are trisaccharides with structures selected from:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ in formulae IV are selected collectively from the group consisting of hydrogen, alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are independently selected from the group consisting of hydrogen, alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; or wherein all groups of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected collectively from the group consisting of acetyl, isobutyryl or propionyl; or wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are independently selected from the group consisting acetyl, isobutyryl or propionyl; and wherein both pure anomers and mixtures of α- and β-anomers of the above mentioned structural variations are claimed.
 10. The composition according to claim 1, wherein at least 50% of the non-water soluble carbohydrates are mono- or oligosaccharides containing at least one amino sugar unit.
 11. The composition according to claim 10, wherein the amino sugar has the structure:

wherein R₁, R₂, R₃, R₄ and R₅ in formulae V are selected collectively from the group consisting of hydrogen, alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl; or wherein R₁, R₂, R₃, R₄ and R₅ are independently selected from the group consisting of hydrogen, alkanoyl, hydroxyl-substituted alkanoyl, and acyloxy-substituted alkanoyl, alkanyl, hydroxysubstituted alkanyl and acyloxy substituted alkanyl, and mono-, di-, tri- or tetra-saccharide derivatives; or wherein all groups of R₁, R₂, R₃, R₄ and R₅ are selected collectively from the group consisting of acetyl, isobutyryl or propionyl; or wherein R₁, R₂, R₃, R₄ and R₅ are independently selected from the group consisting acetyl, isobutyryl or propionyl; and wherein both pure anomers and mixtures of anomers such as α- and β-anomer centres of the above mentioned structural variations are claimed.
 12. The composition according to claim 2, wherein the release of one or more active pharmaceutical ingredients is controlled by mixing non-water soluble carbohydrates with different hydrophobicity by alteration of the substitutions on the carbohydrate hydroxyl groups.
 13. The composition according to claim 2, wherein the active pharmaceutical ingredient is selected from a protein, a peptide, a nucleoprotein, a mucoprotein, a lipoprotein, or a synthetic polypeptide.
 14. The composition according to claim 2, wherein the active pharmaceutical ingredient is selected from a protein, which is a human growth hormone, fibroblast growth factor (FGF), erythropoietin (EPO), platelet derived growth factor (PDGF), granulocyte colony stimulating factor (g-CSF), bovine somatotropin (BST), tumor necrosis factor (TNF), transforming growth factor-beta (TGF-Beta), a cytokine, an interleukin, insulin, or interferon.
 15. The composition according to claim 2, wherein the active pharmaceutical ingredient is selected from nucleic acids, nucleotides, nucleosides, oligonucleotides, DNA, RNA or fragments thereof.
 16. The composition according to claim 2, wherein the active pharmaceutical ingredient is a small inorganic or organic drug molecule.
 17. The composition according to claim 2, wherein the active pharmaceutical ingredient is a chemotherapeutic drug for treatment of cancer.
 18. The composition according to claim 2, wherein the active pharmaceutical ingredients is a chemotherapeutic drug selected from the class of compounds that are anti-metabolites, anti-microtubule agents, topoisomerase inhibitors, cytotoxic antibiotics, alkylating agents, checkpoint inhibitors, or a radiosensitizer, or a photosensitizer.
 19. The composition according to claim 2, wherein the active pharmaceutical ingredient is a drug that modulates an immune response.
 20. The composition according to claim 2, wherein the active pharmaceutical ingredient enhances the effect of radiotherapy, photodynamic therapy (PDT), hyperthermia based treatments such as high-intensity focused ultrasound (HIFU), radiofrequency thermal ablation (RFA), laser-therapy, or laser-induced interstitial thermotherapy (LITT).
 21. The composition according to claim 2, wherein the active pharmaceutical ingredient is an anesthetic.
 22. The composition according to claim 2, wherein the active pharmaceutical ingredient is formulated in a nanoparticle or microsphere that is dispersed in the composition.
 23. The composition according to claim 1, wherein the composition comprises contrast agents that makes the composition visible by PET imaging, SPECT imaging, Ultrasound imaging, CT imaging, x-ray imaging, fluoroscopy imaging, fluorescence imaging, or OCT imaging.
 24. The composition according to claim 1, wherein the composition comprises organic radioisotopes or inorganic radionuclides for use as internal radiotherapy such as brachytherapy or in imaging of tissue in humans or animals.
 25. The composition according to claim 1, which is administered to the human or animal body through a syringe, an endoscope or a bronchoscope to the target tissue preferably wherein the composition after insertion into the human or animal body constitutes a medical or surgical implant for tissue or surgical adhesion which preferably is wound dressing, a hemostat, enhances tissue regeneration, is a void filler.
 26. A medical or surgical implant comprising a composition according to claim 1, wherein the composition is part of a sprayable composition. 